Agents that inhibit PROTEIN KINASES.
An serine-threonine protein kinase that requires the presence of physiological concentrations of CALCIUM and membrane PHOSPHOLIPIDS. The additional presence of DIACYLGLYCEROLS markedly increases its sensitivity to both calcium and phospholipids. The sensitivity of the enzyme can also be increased by PHORBOL ESTERS and it is believed that protein kinase C is the receptor protein of tumor-promoting phorbol esters.
A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein.
A group of enzymes that are dependent on CYCLIC AMP and catalyze the phosphorylation of SERINE or THREONINE residues on proteins. Included under this category are two cyclic-AMP-dependent protein kinase subtypes, each of which is defined by its subunit composition.
An indolocarbazole that is a potent PROTEIN KINASE C inhibitor which enhances cAMP-mediated responses in human neuroblastoma cells. (Biochem Biophys Res Commun 1995;214(3):1114-20)
The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.
A specific protein kinase C inhibitor, which inhibits superoxide release from human neutrophils (PMN) stimulated with phorbol myristate acetate or synthetic diacylglycerol.
Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.
A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors.
A CALMODULIN-dependent enzyme that catalyzes the phosphorylation of proteins. This enzyme is also sometimes dependent on CALCIUM. A wide range of proteins can act as acceptor, including VIMENTIN; SYNAPSINS; GLYCOGEN SYNTHASE; MYOSIN LIGHT CHAINS; and the MICROTUBULE-ASSOCIATED PROTEINS. (From Enzyme Nomenclature, 1992, p277)
A superfamily of PROTEIN-SERINE-THREONINE KINASES that are activated by diverse stimuli via protein kinase cascades. They are the final components of the cascades, activated by phosphorylation by MITOGEN-ACTIVATED PROTEIN KINASE KINASES, which in turn are activated by mitogen-activated protein kinase kinase kinases (MAP KINASE KINASE KINASES).
A mitogen-activated protein kinase subfamily that regulates a variety of cellular processes including CELL GROWTH PROCESSES; CELL DIFFERENTIATION; APOPTOSIS; and cellular responses to INFLAMMATION. The P38 MAP kinases are regulated by CYTOKINE RECEPTORS and can be activated in response to bacterial pathogens.
A group of compounds with the heterocyclic ring structure of benzo(c)pyridine. The ring structure is characteristic of the group of opium alkaloids such as papaverine. (From Stedman, 25th ed)
Phosphotransferases that catalyzes the conversion of 1-phosphatidylinositol to 1-phosphatidylinositol 3-phosphate. Many members of this enzyme class are involved in RECEPTOR MEDIATED SIGNAL TRANSDUCTION and regulation of vesicular transport with the cell. Phosphatidylinositol 3-Kinases have been classified both according to their substrate specificity and their mode of action within the cell.
Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1, activation by ions (activators); 2, activation by cofactors (coenzymes); and 3, conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme.
Organic nitrogenous bases. Many alkaloids of medical importance occur in the animal and vegetable kingdoms, and some have been synthesized. (Grant & Hackh's Chemical Dictionary, 5th ed)
An intracellular signaling system involving the MAP kinase cascades (three-membered protein kinase cascades). Various upstream activators, which act in response to extracellular stimuli, trigger the cascades by activating the first member of a cascade, MAP KINASE KINASE KINASES; (MAPKKKs). Activated MAPKKKs phosphorylate MITOGEN-ACTIVATED PROTEIN KINASE KINASES which in turn phosphorylate the MITOGEN-ACTIVATED PROTEIN KINASES; (MAPKs). The MAPKs then act on various downstream targets to affect gene expression. In mammals, there are several distinct MAP kinase pathways including the ERK (extracellular signal-regulated kinase) pathway, the SAPK/JNK (stress-activated protein kinase/c-jun kinase) pathway, and the p38 kinase pathway. There is some sharing of components among the pathways depending on which stimulus originates activation of the cascade.
The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.
Group of alkaloids containing a benzylpyrrole group (derived from TRYPTOPHAN)
Protein kinases that catalyze the PHOSPHORYLATION of TYROSINE residues in proteins with ATP or other nucleotides as phosphate donors.
A proline-directed serine/threonine protein kinase which mediates signal transduction from the cell surface to the nucleus. Activation of the enzyme by phosphorylation leads to its translocation into the nucleus where it acts upon specific transcription factors. p40 MAPK and p41 MAPK are isoforms.
Benzo-indoles similar to CARBOLINES which are pyrido-indoles. In plants, carbazoles are derived from indole and form some of the INDOLE ALKALOIDS.
A serine-threonine protein kinase family whose members are components in protein kinase cascades activated by diverse stimuli. These MAPK kinases phosphorylate MITOGEN-ACTIVATED PROTEIN KINASES and are themselves phosphorylated by MAP KINASE KINASE KINASES. JNK kinases (also known as SAPK kinases) are a subfamily.
A 44-kDa extracellular signal-regulated MAP kinase that may play a role the initiation and regulation of MEIOSIS; MITOSIS; and postmitotic functions in differentiated cells. It phosphorylates a number of TRANSCRIPTION FACTORS; and MICROTUBULE-ASSOCIATED PROTEINS.
Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.
A phorbol ester found in CROTON OIL with very effective tumor promoting activity. It stimulates the synthesis of both DNA and RNA.
A subgroup of mitogen-activated protein kinases that activate TRANSCRIPTION FACTOR AP-1 via the phosphorylation of C-JUN PROTEINS. They are components of intracellular signaling pathways that regulate CELL PROLIFERATION; APOPTOSIS; and CELL DIFFERENTIATION.
A group of cyclic GMP-dependent enzymes that catalyze the phosphorylation of SERINE or THREONINE residues of proteins.
An adenine nucleotide containing one phosphate group which is esterified to both the 3'- and 5'-positions of the sugar moiety. It is a second messenger and a key intracellular regulator, functioning as a mediator of activity for a number of hormones, including epinephrine, glucagon, and ACTH.
A cytoplasmic serine threonine kinase involved in regulating CELL DIFFERENTIATION and CELLULAR PROLIFERATION. Overexpression of this enzyme has been shown to promote PHOSPHORYLATION of BCL-2 PROTO-ONCOGENE PROTEINS and chemoresistance in human acute leukemia cells.
Benzopyrroles with the nitrogen at the number one carbon adjacent to the benzyl portion, in contrast to ISOINDOLES which have the nitrogen away from the six-membered ring.
A ubiquitously expressed protein kinase that is involved in a variety of cellular SIGNAL PATHWAYS. Its activity is regulated by a variety of signaling protein tyrosine kinase.
Established cell cultures that have the potential to propagate indefinitely.
A PROTEIN-TYROSINE KINASE family that was originally identified by homology to the Rous sarcoma virus ONCOGENE PROTEIN PP60(V-SRC). They interact with a variety of cell-surface receptors and participate in intracellular signal transduction pathways. Oncogenic forms of src-family kinases can occur through altered regulation or expression of the endogenous protein and by virally encoded src (v-src) genes.
Compounds with a six membered aromatic ring containing NITROGEN. The saturated version is PIPERIDINES.
Structurally related forms of an enzyme. Each isoenzyme has the same mechanism and classification, but differs in its chemical, physical, or immunological characteristics.
Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.
The rate dynamics in chemical or physical systems.
Intracellular signaling protein kinases that play a signaling role in the regulation of cellular energy metabolism. Their activity largely depends upon the concentration of cellular AMP which is increased under conditions of low energy or metabolic stress. AMP-activated protein kinases modify enzymes involved in LIPID METABOLISM, which in turn provide substrates needed to convert AMP into ATP.
A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.
An isoflavonoid derived from soy products. It inhibits PROTEIN-TYROSINE KINASE and topoisomerase-II (DNA TOPOISOMERASES, TYPE II); activity and is used as an antineoplastic and antitumor agent. Experimentally, it has been shown to induce G2 PHASE arrest in human and murine cell lines and inhibits PROTEIN-TYROSINE KINASE.
Protein kinases that control cell cycle progression in all eukaryotes and require physical association with CYCLINS to achieve full enzymatic activity. Cyclin-dependent kinases are regulated by phosphorylation and dephosphorylation events.
Proteins and peptides that are involved in SIGNAL TRANSDUCTION within the cell. Included here are peptides and proteins that regulate the activity of TRANSCRIPTION FACTORS and cellular processes in response to signals from CELL SURFACE RECEPTORS. Intracellular signaling peptide and proteins may be part of an enzymatic signaling cascade or act through binding to and modifying the action of other signaling factors.
A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes.
The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.
A group of phenyl benzopyrans named for having structures like FLAVONES.
A protein kinase C subtype that was originally characterized as a CALCIUM-independent, serine-threonine kinase that is activated by PHORBOL ESTERS and DIACYLGLYCEROLS. It is targeted to specific cellular compartments in response to extracellular signals that activate G-PROTEIN-COUPLED RECEPTORS; TYROSINE KINASE RECEPTORS; and intracellular protein tyrosine kinase.
Phosphoprotein with protein kinase activity that functions in the G2/M phase transition of the CELL CYCLE. It is the catalytic subunit of the MATURATION-PROMOTING FACTOR and complexes with both CYCLIN A and CYCLIN B in mammalian cells. The maximal activity of cyclin-dependent kinase 1 is achieved when it is fully dephosphorylated.
PKC beta encodes two proteins (PKCB1 and PKCBII) generated by alternative splicing of C-terminal exons. It is widely distributed with wide-ranging roles in processes such as B-cell receptor regulation, oxidative stress-induced apoptosis, androgen receptor-dependent transcriptional regulation, insulin signaling, and endothelial cell proliferation.
A ubiquitous casein kinase that is comprised of two distinct catalytic subunits and dimeric regulatory subunit. Casein kinase II has been shown to phosphorylate a large number of substrates, many of which are proteins involved in the regulation of gene expression.
Compounds containing 1,3-diazole, a five membered aromatic ring containing two nitrogen atoms separated by one of the carbons. Chemically reduced ones include IMIDAZOLINES and IMIDAZOLIDINES. Distinguish from 1,2-diazole (PYRAZOLES).
The relationship between the dose of an administered drug and the response of the organism to the drug.
A cyclin-dependent kinase inhibitor that coordinates the activation of CYCLIN and CYCLIN-DEPENDENT KINASES during the CELL CYCLE. It interacts with active CYCLIN D complexed to CYCLIN-DEPENDENT KINASE 4 in proliferating cells, while in arrested cells it binds and inhibits CYCLIN E complexed to CYCLIN-DEPENDENT KINASE 2.
Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes.
The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES.
RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.
Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely.
One of the mechanisms by which CELL DEATH occurs (compare with NECROSIS and AUTOPHAGOCYTOSIS). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA; (DNA FRAGMENTATION); at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth.
A protein-serine-threonine kinase that is activated by PHOSPHORYLATION in response to GROWTH FACTORS or INSULIN. It plays a major role in cell metabolism, growth, and survival as a core component of SIGNAL TRANSDUCTION. Three isoforms have been described in mammalian cells.
A multifunctional calcium-calmodulin-dependent protein kinase subtype that occurs as an oligomeric protein comprised of twelve subunits. It differs from other enzyme subtypes in that it lacks a phosphorylatable activation domain that can respond to CALCIUM-CALMODULIN-DEPENDENT PROTEIN KINASE KINASE.
A cyclin-dependent kinase inhibitor that mediates TUMOR SUPPRESSOR PROTEIN P53-dependent CELL CYCLE arrest. p21 interacts with a range of CYCLIN-DEPENDENT KINASES and associates with PROLIFERATING CELL NUCLEAR ANTIGEN and CASPASE 3.
Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity.
A group of compounds that contain the structure SO2NH2.
A mitogen-activated protein kinase subfamily that is widely expressed and plays a role in regulation of MEIOSIS; MITOSIS; and post mitotic functions in differentiated cells. The extracellular signal regulated MAP kinases are regulated by a broad variety of CELL SURFACE RECEPTORS and can be activated by certain CARCINOGENS.
Derivatives of the steroid androstane having two double bonds at any site in any of the rings.
A cell line derived from cultured tumor cells.
An abundant 43-kDa mitogen-activated protein kinase kinase subtype with specificity for MITOGEN-ACTIVATED PROTEIN KINASE 1 and MITOGEN-ACTIVATED PROTEIN KINASE 3.
The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.
Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.
A specific inhibitor of phosphoserine/threonine protein phosphatase 1 and 2a. It is also a potent tumor promoter. (Thromb Res 1992;67(4):345-54 & Cancer Res 1993;53(2):239-41)
Transport proteins that carry specific substances in the blood or across cell membranes.
A phorbol ester found in CROTON OIL which, in addition to being a potent skin tumor promoter, is also an effective activator of calcium-activated, phospholipid-dependent protein kinase (protein kinase C). Due to its activation of this enzyme, phorbol 12,13-dibutyrate profoundly affects many different biological systems.
Tumor-promoting compounds obtained from CROTON OIL (Croton tiglium). Some of these are used in cell biological experiments as activators of protein kinase C.
Mitogen-activated protein kinase kinase kinases (MAPKKKs) are serine-threonine protein kinases that initiate protein kinase signaling cascades. They phosphorylate MITOGEN-ACTIVATED PROTEIN KINASE KINASES; (MAPKKs) which in turn phosphorylate MITOGEN-ACTIVATED PROTEIN KINASES; (MAPKs).
The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION.
A group of protein-serine-threonine kinases that was originally identified as being responsible for the PHOSPHORYLATION of CASEINS. They are ubiquitous enzymes that have a preference for acidic proteins. Casein kinases play a role in SIGNAL TRANSDUCTION by phosphorylating a variety of regulatory cytoplasmic and regulatory nuclear proteins.
A group of intracellular-signaling serine threonine kinases that bind to RHO GTP-BINDING PROTEINS. They were originally found to mediate the effects of rhoA GTP-BINDING PROTEIN on the formation of STRESS FIBERS and FOCAL ADHESIONS. Rho-associated kinases have specificity for a variety of substrates including MYOSIN-LIGHT-CHAIN PHOSPHATASE and LIM KINASES.
A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts.
Proteins prepared by recombinant DNA technology.
A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from GLYCINE or THREONINE. It is involved in the biosynthesis of PURINES; PYRIMIDINES; and other amino acids.
Substances that inhibit or prevent the proliferation of NEOPLASMS.
The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.
An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter.
A group of enzymes removing the SERINE- or THREONINE-bound phosphate groups from a wide range of phosphoproteins, including a number of enzymes which have been phosphorylated under the action of a kinase. (Enzyme Nomenclature, 1992)
A family of serine-threonine kinases that bind to and are activated by MONOMERIC GTP-BINDING PROTEINS such as RAC GTP-BINDING PROTEINS and CDC42 GTP-BINDING PROTEIN. They are intracellular signaling kinases that play a role the regulation of cytoskeletal organization.
The complex series of phenomena, occurring between the end of one CELL DIVISION and the end of the next, by which cellular material is duplicated and then divided between two daughter cells. The cell cycle includes INTERPHASE, which includes G0 PHASE; G1 PHASE; S PHASE; and G2 PHASE, and CELL DIVISION PHASE.
A cyclic AMP-dependent protein kinase subtype primarily found in particulate subcellular fractions. They are tetrameric proteins that contain two catalytic subunits and two type II-specific regulatory subunits.
A non-essential amino acid. In animals it is synthesized from PHENYLALANINE. It is also the precursor of EPINEPHRINE; THYROID HORMONES; and melanin.
A dsRNA-activated cAMP-independent protein serine/threonine kinase that is induced by interferon. In the presence of dsRNA and ATP, the kinase autophosphorylates on several serine and threonine residues. The phosphorylated enzyme catalyzes the phosphorylation of the alpha subunit of EUKARYOTIC INITIATION FACTOR-2, leading to the inhibition of protein synthesis.
Elements of limited time intervals, contributing to particular results or situations.
Four carbon unsaturated hydrocarbons containing two double bonds.
Organic compounds containing the -CN radical. The concept is distinguished from CYANIDES, which denotes inorganic salts of HYDROGEN CYANIDE.
A family of protein serine/threonine kinases which act as intracellular signalling intermediates. Ribosomal protein S6 kinases are activated through phosphorylation in response to a variety of HORMONES and INTERCELLULAR SIGNALING PEPTIDES AND PROTEINS. Phosphorylation of RIBOSOMAL PROTEIN S6 by enzymes in this class results in increased expression of 5' top MRNAs. Although specific for RIBOSOMAL PROTEIN S6 members of this class of kinases can act on a number of substrates within the cell. The immunosuppressant SIROLIMUS inhibits the activation of ribosomal protein S6 kinases.
A strain of albino rat used widely for experimental purposes because of its calmness and ease of handling. It was developed by the Sprague-Dawley Animal Company.
The parts of a macromolecule that directly participate in its specific combination with another molecule.
Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation.
Azoles of one NITROGEN and two double bonds that have aromatic chemical properties.
Compounds of the general formula R-O-R arranged in a ring or crown formation.
Cell lines whose original growing procedure consisted being transferred (T) every 3 days and plated at 300,000 cells per plate (J Cell Biol 17:299-313, 1963). Lines have been developed using several different strains of mice. Tissues are usually fibroblasts derived from mouse embryos but other types and sources have been developed as well. The 3T3 lines are valuable in vitro host systems for oncogenic virus transformation studies, since 3T3 cells possess a high sensitivity to CONTACT INHIBITION.
A class of cellular receptors that have an intrinsic PROTEIN-TYROSINE KINASE activity.
A mitogen-activated protein kinase kinase with specificity for JNK MITOGEN-ACTIVATED PROTEIN KINASES; P38 MITOGEN-ACTIVATED PROTEIN KINASES and the RETINOID X RECEPTORS. It takes part in a SIGNAL TRANSDUCTION pathway that is activated in response to cellular stress.
A cell surface receptor involved in regulation of cell growth and differentiation. It is specific for EPIDERMAL GROWTH FACTOR and EGF-related peptides including TRANSFORMING GROWTH FACTOR ALPHA; AMPHIREGULIN; and HEPARIN-BINDING EGF-LIKE GROWTH FACTOR. The binding of ligand to the receptor causes activation of its intrinsic tyrosine kinase activity and rapid internalization of the receptor-ligand complex into the cell.
Recombinant proteins produced by the GENETIC TRANSLATION of fused genes formed by the combination of NUCLEIC ACID REGULATORY SEQUENCES of one or more genes with the protein coding sequences of one or more genes.
A negative regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (GENE EXPRESSION REGULATION), mRNAs (RNA, MESSENGER), and proteins.
The biosynthesis of RNA carried out on a template of DNA. The biosynthesis of DNA from an RNA template is called REVERSE TRANSCRIPTION.
A group of enzymes that transfers a phosphate group onto an alcohol group acceptor. EC 2.7.1.
Two-ring crystalline hydrocarbons isolated from coal tar. They are used as intermediates in chemical synthesis, as insect repellents, fungicides, lubricants, preservatives, and, formerly, as topical antiseptics.
Potent activator of the adenylate cyclase system and the biosynthesis of cyclic AMP. From the plant COLEUS FORSKOHLII. Has antihypertensive, positive inotropic, platelet aggregation inhibitory, and smooth muscle relaxant activities; also lowers intraocular pressure and promotes release of hormones from the pituitary gland.
An aspect of protein kinase (EC in which serine residues in protamines and histones are phosphorylated in the presence of ATP.
Proteins that control the CELL DIVISION CYCLE. This family of proteins includes a wide variety of classes, including CYCLIN-DEPENDENT KINASES, mitogen-activated kinases, CYCLINS, and PHOSPHOPROTEIN PHOSPHATASES as well as their putative substrates such as chromatin-associated proteins, CYTOSKELETAL PROTEINS, and TRANSCRIPTION FACTORS.
Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (CELL NUCLEOLUS). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the ENDOPLASMIC RETICULUM. A cell may contain more than one nucleus. (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed)
All of the processes involved in increasing CELL NUMBER including CELL DIVISION.
3-Phenylchromones. Isomeric form of FLAVONOIDS in which the benzene group is attached to the 3 position of the benzopyran ring instead of the 2 position.
Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases.
Immunologic method used for detecting or quantifying immunoreactive substances. The substance is identified by first immobilizing it by blotting onto a membrane and then tagging it with labeled antibodies.
Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action in enzyme synthesis.
Guanosine cyclic 3',5'-(hydrogen phosphate). A guanine nucleotide containing one phosphate group which is esterified to the sugar moiety in both the 3'- and 5'-positions. It is a cellular regulatory agent and has been described as a second messenger. Its levels increase in response to a variety of hormones, including acetylcholine, insulin, and oxytocin and it has been found to activate specific protein kinases. (From Merck Index, 11th ed)
The first continuously cultured human malignant CELL LINE, derived from the cervical carcinoma of Henrietta Lacks. These cells are used for VIRUS CULTIVATION and antitumor drug screening assays.
Compounds of four rings containing a nitrogen. They are biosynthesized from reticuline via rearrangement of scoulerine. They are similar to BENZYLISOQUINOLINES. Members include chelerythrine and sanguinarine.
A family of highly conserved serine-threonine kinases that are involved in the regulation of MITOSIS. They are involved in many aspects of cell division, including centrosome duplication, SPINDLE APPARATUS formation, chromosome alignment, attachment to the spindle, checkpoint activation, and CYTOKINESIS.
The level of protein structure in which combinations of secondary protein structures (alpha helices, beta sheets, loop regions, and motifs) pack together to form folded shapes called domains. Disulfide bridges between cysteines in two different parts of the polypeptide chain along with other interactions between the chains play a role in the formation and stabilization of tertiary structure. Small proteins usually consist of only one domain but larger proteins may contain a number of domains connected by segments of polypeptide chain which lack regular secondary structure.
The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability.
A 38-kDa mitogen-activated protein kinase that is abundantly expressed in a broad variety of cell types. It is involved in the regulation of cellular stress responses as well as the control of proliferation and survival of many cell types. The kinase activity of the enzyme is inhibited by the pyridinyl-imidazole compound SB 203580.
Domesticated bovine animals of the genus Bos, usually kept on a farm or ranch and used for the production of meat or dairy products or for heavy labor.
A glycogen synthase kinase that was originally described as a key enzyme involved in glycogen metabolism. It regulates a diverse array of functions such as CELL DIVISION, microtubule function and APOPTOSIS.
Intracellular fluid from the cytoplasm after removal of ORGANELLES and other insoluble cytoplasmic components.
Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment.
Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules.
An enzyme that phosphorylates myosin light chains in the presence of ATP to yield myosin-light chain phosphate and ADP, and requires calcium and CALMODULIN. The 20-kDa light chain is phosphorylated more rapidly than any other acceptor, but light chains from other myosins and myosin itself can act as acceptors. The enzyme plays a central role in the regulation of smooth muscle contraction.
Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.
A large family of regulatory proteins that function as accessory subunits to a variety of CYCLIN-DEPENDENT KINASES. They generally function as ENZYME ACTIVATORS that drive the CELL CYCLE through transitions between phases. A subset of cyclins may also function as transcriptional regulators.
A family of synthetic protein tyrosine kinase inhibitors. They selectively inhibit receptor autophosphorylation and are used to study receptor function.
A serine-threonine protein kinase that, when activated by DNA, phosphorylates several DNA-binding protein substrates including the TUMOR SUPPRESSOR PROTEIN P53 and a variety of TRANSCRIPTION FACTORS.
A purine that is an isomer of ADENINE (6-aminopurine).
The degree of similarity between sequences of amino acids. This information is useful for the analyzing genetic relatedness of proteins and species.
The species Oryctolagus cuniculus, in the family Leporidae, order LAGOMORPHA. Rabbits are born in burrows, furless, and with eyes and ears closed. In contrast with HARES, rabbits have 22 chromosome pairs.
Azoles of two nitrogens at the 1,2 positions, next to each other, in contrast with IMIDAZOLES in which they are at the 1,3 positions.
A long-acting derivative of cyclic AMP. It is an activator of cyclic AMP-dependent protein kinase, but resistant to degradation by cyclic AMP phosphodiesterase.
A family of cell cycle-dependent kinases that are related in structure to CDC28 PROTEIN KINASE; S CEREVISIAE; and the CDC2 PROTEIN KINASE found in mammalian species.
Highly conserved protein-serine threonine kinases that phosphorylate and activate a group of AGC protein kinases, especially in response to the production of the SECOND MESSENGERS, phosphatidylinositol 3,4,-biphosphate (PtdIns(3,4)P2) and phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3).
A transferase that catalyzes formation of PHOSPHOCREATINE from ATP + CREATINE. The reaction stores ATP energy as phosphocreatine. Three cytoplasmic ISOENZYMES have been identified in human tissues: the MM type from SKELETAL MUSCLE, the MB type from myocardial tissue and the BB type from nervous tissue as well as a mitochondrial isoenzyme. Macro-creatine kinase refers to creatine kinase complexed with other serum proteins.
Systems in which an intracellular signal is generated in response to an intercellular primary messenger such as a hormone or neurotransmitter. They are intermediate signals in cellular processes such as metabolism, secretion, contraction, phototransduction, and cell growth. Examples of second messenger systems are the adenyl cyclase-cyclic AMP system, the phosphatidylinositol diphosphate-inositol triphosphate system, and the cyclic GMP system.
A positive regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (GENE EXPRESSION REGULATION), mRNAs (RNA, MESSENGER), and proteins.
The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells.
Nucleotides in which the base moiety is substituted with one or more sulfur atoms.
The insertion of recombinant DNA molecules from prokaryotic and/or eukaryotic sources into a replicating vehicle, such as a plasmid or virus vector, and the introduction of the resultant hybrid molecules into recipient cells without altering the viability of those cells.
An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins.
ATP:pyruvate 2-O-phosphotransferase. A phosphotransferase that catalyzes reversibly the phosphorylation of pyruvate to phosphoenolpyruvate in the presence of ATP. It has four isozymes (L, R, M1, and M2). Deficiency of the enzyme results in hemolytic anemia. EC
An amino acid that occurs in endogenous proteins. Tyrosine phosphorylation and dephosphorylation plays a role in cellular signal transduction and possibly in cell growth control and carcinogenesis.
Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors.
Proteins found in the nucleus of a cell. Do not confuse with NUCLEOPROTEINS which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus.
Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.
The phenotypic manifestation of a gene or genes by the processes of GENETIC TRANSCRIPTION and GENETIC TRANSLATION.
The movement of materials (including biochemical substances and drugs) through a biological system at the cellular level. The transport can be across cell membranes and epithelial layers. It also can occur within intracellular compartments and extracellular compartments.
A family of ribosomal protein S6 kinases that are structurally distinguished from RIBOSOMAL PROTEIN S6 KINASES, 70-KDA by their apparent molecular size and the fact they contain two functional kinase domains. Although considered RIBOSOMAL PROTEIN S6 KINASES, members of this family are activated via the MAP KINASE SIGNALING SYSTEM and have been shown to act on a diverse array of substrates that are involved in cellular regulation such as RIBOSOMAL PROTEIN S6 and CAMP RESPONSE ELEMENT-BINDING PROTEIN.
The action of a drug in promoting or enhancing the effectiveness of another drug.
Serologic tests in which a positive reaction manifested by visible CHEMICAL PRECIPITATION occurs when a soluble ANTIGEN reacts with its precipitins, i.e., ANTIBODIES that can form a precipitate.
An enzyme of the transferase class that uses ATP to catalyze the phosphorylation of diacylglycerol to a phosphatidate. EC
A c-jun amino-terminal kinase that is activated by environmental stress and pro-inflammatory cytokines. Several isoforms of the protein with molecular sizes of 43 and 48 KD exist due to multiple ALTERNATIVE SPLICING.
Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs.
Ubiquitous, inducible, nuclear transcriptional activator that binds to enhancer elements in many different cell types and is activated by pathogenic stimuli. The NF-kappa B complex is a heterodimer composed of two DNA-binding subunits: NF-kappa B1 and relA.
The phosphoric acid ester of serine.
A strain of albino rat developed at the Wistar Institute that has spread widely at other institutions. This has markedly diluted the original strain.
A protein serine-threonine kinase that catalyzes the PHOSPHORYLATION of I KAPPA B PROTEINS. This enzyme also activates the transcription factor NF-KAPPA B and is composed of alpha and beta catalytic subunits, which are protein kinases and gamma, a regulatory subunit.
A 44 kDa mitogen-activated protein kinase kinase with specificity for MITOGEN-ACTIVATED PROTEIN KINASE 1 and MITOGEN-ACTIVATED PROTEIN KINASE 3.
A 195-kDa MAP kinase kinase kinase with broad specificity for MAP KINASE KINASES. It is found localized in the CYTOSKELETON and can activate a variety of MAP kinase-dependent pathways.
Short sequences (generally about 10 base pairs) of DNA that are complementary to sequences of messenger RNA and allow reverse transcriptases to start copying the adjacent sequences of mRNA. Primers are used extensively in genetic and molecular biology techniques.
The sum of the weight of all the atoms in a molecule.
A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels.
A CELL LINE derived from a PHEOCHROMOCYTOMA of the rat ADRENAL MEDULLA. PC12 cells stop dividing and undergo terminal differentiation when treated with NERVE GROWTH FACTOR, making the line a useful model system for NERVE CELL differentiation.
Genetically engineered MUTAGENESIS at a specific site in the DNA molecule that introduces a base substitution, or an insertion or deletion.
Filamentous proteins that are the main constituent of the thin filaments of muscle fibers. The filaments (known also as filamentous or F-actin) can be dissociated into their globular subunits; each subunit is composed of a single polypeptide 375 amino acids long. This is known as globular or G-actin. In conjunction with MYOSINS, actin is responsible for the contraction and relaxation of muscle.
A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS.
DNA sequences which are recognized (directly or indirectly) and bound by a DNA-dependent RNA polymerase during the initiation of transcription. Highly conserved sequences within the promoter include the Pribnow box in bacteria and the TATA BOX in eukaryotes.
An enzyme that catalyzes the conversion of phosphatidylinositol (PHOSPHATIDYLINOSITOLS) to phosphatidylinositol 4-phosphate, the first committed step in the biosynthesis of phosphatidylinositol 4,5-bisphosphate.
A variation of the PCR technique in which cDNA is made from RNA via reverse transcription. The resultant cDNA is then amplified using standard PCR protocols.
Members of the class of compounds composed of AMINO ACIDS joined together by peptide bonds between adjacent amino acids into linear, branched or cyclical structures. OLIGOPEPTIDES are composed of approximately 2-12 amino acids. Polypeptides are composed of approximately 13 or more amino acids. PROTEINS are linear polypeptides that are normally synthesized on RIBOSOMES.
Small double-stranded, non-protein coding RNAs (21-31 nucleotides) involved in GENE SILENCING functions, especially RNA INTERFERENCE (RNAi). Endogenously, siRNAs are generated from dsRNAs (RNA, DOUBLE-STRANDED) by the same ribonuclease, Dicer, that generates miRNAs (MICRORNAS). The perfect match of the siRNAs' antisense strand to their target RNAs mediates RNAi by siRNA-guided RNA cleavage. siRNAs fall into different classes including trans-acting siRNA (tasiRNA), repeat-associated RNA (rasiRNA), small-scan RNA (scnRNA), and Piwi protein-interacting RNA (piRNA) and have different specific gene silencing functions.
An increase in the rate of synthesis of an enzyme due to the presence of an inducer which acts to derepress the gene responsible for enzyme synthesis.
An enzyme that catalyzes the conversion of ATP and thymidine to ADP and thymidine 5'-phosphate. Deoxyuridine can also act as an acceptor and dGTP as a donor. (From Enzyme Nomenclature, 1992) EC
A serine threonine kinase that controls a wide range of growth-related cellular processes. The protein is referred to as the target of RAPAMYCIN due to the discovery that SIROLIMUS (commonly known as rapamycin) forms an inhibitory complex with TACROLIMUS BINDING PROTEIN 1A that blocks the action of its enzymatic activity.
A potent inhibitor of CYCLIN-DEPENDENT KINASES in G1 PHASE and S PHASE. In humans, aberrant expression of p57 is associated with various NEOPLASMS as well as with BECKWITH-WIEDEMANN SYNDROME.
Five-membered heterocyclic ring structures containing an oxygen in the 1-position and a nitrogen in the 3-position, in distinction from ISOXAZOLES where they are at the 1,2 positions.
The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.
Electrophoresis in which a polyacrylamide gel is used as the diffusion medium.
A protein that has been shown to function as a calcium-regulated transcription factor as well as a substrate for depolarization-activated CALCIUM-CALMODULIN-DEPENDENT PROTEIN KINASES. This protein functions to integrate both calcium and cAMP signals.
The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM.
A key regulator of CELL CYCLE progression. It partners with CYCLIN E to regulate entry into S PHASE and also interacts with CYCLIN A to phosphorylate RETINOBLASTOMA PROTEIN. Its activity is inhibited by CYCLIN-DEPENDENT KINASE INHIBITOR P27 and CYCLIN-DEPENDENT KINASE INHIBITOR P21.
A type of CELL NUCLEUS division by means of which the two daughter nuclei normally receive identical complements of the number of CHROMOSOMES of the somatic cells of the species.
A 6-kDa polypeptide growth factor initially discovered in mouse submaxillary glands. Human epidermal growth factor was originally isolated from urine based on its ability to inhibit gastric secretion and called urogastrone. Epidermal growth factor exerts a wide variety of biological effects including the promotion of proliferation and differentiation of mesenchymal and EPITHELIAL CELLS. It is synthesized as a transmembrane protein which can be cleaved to release a soluble active form.
The muscle tissue of the HEART. It is composed of striated, involuntary muscle cells (MYOCYTES, CARDIAC) connected to form the contractile pump to generate blood flow.
Serum glycoprotein produced by activated MACROPHAGES and other mammalian MONONUCLEAR LEUKOCYTES. It has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. Also known as TNF-alpha, it is only 30% homologous to TNF-beta (LYMPHOTOXIN), but they share TNF RECEPTORS.

CCAAT/enhancer-binding protein beta is an accessory factor for the glucocorticoid response from the cAMP response element in the rat phosphoenolpyruvate carboxykinase gene promoter. (1/8892)

The cyclic AMP response element (CRE) of the rat phosphoenolpyruvate carboxykinase (PEPCK) gene promoter is required for a complete glucocorticoid response. Proteins known to bind the PEPCK CRE include the CRE-binding protein (CREB) and members of the CCAAT/enhancer-binding protein (C/EBP) family. We took two different approaches to determine which of these proteins provides the accessory factor activity for the glucocorticoid response from the PEPCK CRE. The first strategy involved replacing the CRE of the PEPCK promoter/chloramphenicol acetyltransferase reporter plasmid (pPL32) with a consensus C/EBP-binding sequence. This construct, termed pDeltaCREC/EBP, binds C/EBPalpha and beta but not CREB, yet it confers a nearly complete glucocorticoid response when transiently transfected into H4IIE rat hepatoma cells. These results suggest that one of the C/EBP family members may be the accessory factor. The second strategy involved co-transfecting H4IIE cells with a pPL32 mutant, in which the CRE was replaced with a GAL4-binding sequence (pDeltaCREGAL4), and various GAL4 DNA-binding domain (DBD) fusion protein expression vectors. Although chimeric proteins consisting of the GAL4 DBD fused to either CREB or C/EBPalpha are able to confer an increase in basal transcription, they do not facilitate the glucocorticoid response. In contrast, a fusion protein consisting of the GAL4 DBD and amino acids 1-118 of C/EBPbeta provides a significant glucocorticoid response. Additional GAL4 fusion studies were done to map the minimal domain of C/EBPbeta needed for accessory factor activity to the glucocorticoid response. Chimeric proteins containing amino acid regions 1-84, 52-118, or 85-118 of C/EBPbeta fused to the GAL4 DBD do not mediate a glucocorticoid response. We conclude that the amino terminus of C/EBPbeta contains a multicomponent domain necessary to confer accessory factor activity to the glucocorticoid response from the CRE of the PEPCK gene promoter.  (+info)

p38 but not p44/42 mitogen-activated protein kinase is required for nitric oxide synthase induction mediated by lipopolysaccharide in RAW 264.7 macrophages. (2/8892)

Protein kinase C (PKC)-alpha, -betaI, and -delta are known to be involved in the lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages. The role of mitogen-activated protein kinases (MAPK) p44/42 and p38 in the LPS effect was studied further. LPS-mediated NO release and the inducible form of NO synthase expression were inhibited by the p38 inhibitor, SB 203580, but not by the MAPK kinase inhibitor, PD 98059. Ten-minute treatment of cells with LPS resulted in the activation of p44/42 MAPK, p38, and c-Jun NH2-terminal kinase. Marked or slight activation, respectively, of p44/42 MAPK or p38 was also seen after 10-min treatment with 12-O-tetradecanoylphorbol-13-acetate, but c-Jun NH2-terminal kinase activation did not occur. Tyrosine kinase inhibitor, genestein, attenuated the LPS-induced activation of both p44/42 MAPK and p38, whereas the PKC inhibitors, Ro 31-8220 and calphostin C, or long-term treatment with 12-O-tetradecanoylphorbol-13-acetate resulted in inhibition of p44/42 MAPK activation, but had only a slight effect on p38 activation, indicating that LPS-mediated PKC activation resulted in the activation of p44/42 MAPK. Nuclear factor-kappaB (NF-kappaB)-specific DNA-protein-binding activity in the nuclear extracts was enhanced by 10-min, 1-h, or 24-h treatment with LPS. Analysis of the proteins involved in NF-kappaB binding showed translocation of p65 from the cytosol to the nucleus after 10-min treatment with LPS. The onset of NF-kappaB activation correlated with the cytosolic degradation of both inhibitory proteins of NF-kappaB, IkappaB-alpha and IkappaB-beta. IkappaB-alpha was resynthesized rapidly after loss (1-h LPS treatment), whereas IkappaB-beta levels were not restored until after 24-h treatment. SB 203580 but not PD 98059 inhibited the LPS-induced stimulation of NF-kappaB DNA-protein binding. Thus, activation of p38 but not p44/42 MAPK by LPS resulted in the stimulation of NF-kappaB-specific DNA-protein binding and the subsequent expression of inducible form of NO synthase and NO release in RAW 264.7 macrophages.  (+info)

Role of interleukin (IL)-2 receptor beta-chain subdomains and Shc in p38 mitogen-activated protein (MAP) kinase and p54 MAP kinase (stress-activated protein Kinase/c-Jun N-terminal kinase) activation. IL-2-driven proliferation is independent of p38 and p54 MAP kinase activation. (3/8892)

We have shown recently that interleukin (IL)-2 activates the mitogen-activated protein (MAP) kinase family members p38 (HOG1/stress-activated protein kinase II) and p54 (c-Jun N-terminal kinase/stress-activated protein kinase I). Furthermore, the p38 MAP kinase inhibitor SB203580 inhibited IL-2-driven T cell proliferation, suggesting that p38 MAP kinase might be involved in mediating proliferative signals. In this study, using transfected BA/F3 cell lines, it is shown that both the acidic domain and the membrane-proximal serine-rich region of the IL-2Rbeta chain are required for p38 and p54 MAP kinase activation and that, as for p42/44 MAP kinase, this activation requires the Tyr338 residue of the acidic domain, the binding site for Shc. It is well established that the acidic domain of the IL-2Rbeta chain is dispensable for IL-2-driven proliferation, and thus our observations suggest that neither p38 nor p54 MAP kinase activation is required for IL-2-driven proliferation of BA/F3 cells. In addition, the tetravalent guanylhydrazone inhibitor of proinflammatory cytokine production, CNI-1493, can block the activation of p54 and p38 MAP kinases by IL-2 but has no effect on IL-2-driven proliferation of BA/F3 cells, activated primary T cells, or a cytotoxic T cell line. Furthermore, our observations provide evidence for the existence of an additional, unknown target of the p38 MAP kinase inhibitor SB203580, the activation of which is essential for mitogenic signaling by IL-2.  (+info)

On the mechanism of histaminergic inhibition of glutamate release in the rat dentate gyrus. (4/8892)

1. Histaminergic depression of excitatory synaptic transmission in the rat dentate gyrus was investigated using extracellular and whole-cell patch-clamp recording techniques in vitro. 2. Application of histamine (10 microM, 5 min) depressed synaptic transmission in the dentate gyrus for 1 h. This depression was blocked by the selective antagonist of histamine H3 receptors, thioperamide (10 microM). 3. The magnitude of the depression caused by histamine was inversely related to the extracellular Ca2+ concentration. Application of the N-type calcium channel blocker omega-conotoxin (0. 5 or 1 microM) or the P/Q-type calcium channel blocker omega-agatoxin (800 nM) did not prevent depression of synaptic transmission by histamine. 4. The potassium channel blocker 4-aminopyridine (4-AP, 100 microM) enhanced synaptic transmission and reduced the depressant effect of histamine (10 microM). 4-AP reduced the effect of histamine more in 2 mM extracellular calcium than in 4 mM extracellular calcium. 5. Histamine (10 microM) did not affect the amplitude of miniature excitatory postsynaptic currents (mEPSCs) and had only a small effect on their frequency. 6. Histaminergic depression was not blocked by an inhibitor of serine/threonine protein kinases, H7 (100 microM), or by an inhibitor of tyrosine kinases, Lavendustin A (10 microM). 7. Application of adenosine (20 microM) or the adenosine A1 agonist N6-cyclopentyladenosine (CPA, 0.3 microM) completely occluded the effect of histamine (10 microM). 8. We conclude that histamine, acting on histamine H3 receptors, inhibits glutamate release by inhibiting presynaptic calcium entry, via a direct G-protein-mediated inhibition of multiple calcium channels. Histamine H3 receptors and adenosine A1 receptors act upon a common final effector to cause presynaptic inhibition.  (+info)

Effect of inhibition of cholesterol synthetic pathway on the activation of Ras and MAP kinase in mesangial cells. (5/8892)

Intermediary metabolites of cholesterol synthetic pathway are involved in cell proliferation. Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, blocks mevalonate synthesis, and has been shown to inhibit mesangial cell proliferation associated with diverse glomerular diseases. Since inhibition of farnesylation and plasma membrane anchorage of the Ras proteins is one suggested mechanism by which lovastatin prevents cellular proliferation, we investigated the effect of lovastatin and key mevalonate metabolites on the activation of mitogen-activated protein kinase (MAP kinase) and Ras in murine glomerular mesangial cells. The preincubation of mesangial cells with lovastatin inhibited the activation of MAP kinase stimulated by either FBS, PDGF, or EGF. Mevalonic acid and farnesyl-pyrophosphate, but not cholesterol or LDL, significantly prevented lovastatin-induced inhibition of agonist-stimulated MAP kinase. Lovastatin inhibited agonist-induced activation of Ras, and mevalonic acid and farnesylpyrophosphate antagonized this effect. Parallel to the MAP kinase and Ras data, lovastatin suppressed cell growth stimulated by serum, and mevalonic acid and farnesylpyrophosphate prevented lovastatin-mediated inhibition of cellular growth. These results suggest that lovastatin, by inhibiting the synthesis of farnesol, a key isoprenoid metabolite of mevalonate, modulates Ras-mediated cell signaling events associated with mesangial cell proliferation.  (+info)

ATP counteracts the rundown of gap junctional channels of rat ventricular myocytes by promoting protein phosphorylation. (6/8892)

1. The degree of cell-to-cell coupling between ventricular myocytes of neonatal rats appeared well preserved when studied in the perforated version of the patch clamp technique or, in double whole-cell conditions, when ATP was present in the patch pipette solution. In contrast, when ATP was omitted, the amplitude of junctional current rapidly declined (rundown). 2. To examine the mechanism(s) of ATP action, an 'internal perfusion technique' was adapted to dual patch clamp conditions, and reintroduction of ATP partially reversed the rundown of junctional channels. 3. Cell-to-cell communication was not preserved by a non-hydrolysable ATP analogue (5'-adenylimidodiphosphate, AMP-PNP), indicating that the effect most probably did not involve direct interaction of ATP with the channel-forming proteins. 4. An ATP analogue supporting protein phosphorylation but not active transport processes (adenosine 5'-O-(3-thiotriphosphate), ATPgammaS) maintained normal intercellular communication, suggesting that the effect was due to kinase activity rather than to altered intracellular Ca2+. 5. A broad spectrum inhibitor of endogenous serine/threonine protein kinases (H7) reversibly reduced the intercellular coupling. A non-specific exogenous protein phosphatase (alkaline phosphatase) mimicked the effects of ATP deprivation. The non-specific inhibition of endogenous protein phosphatases resulted in the preservation of substantial cell-to-cell communication in ATP-free conditions. 6. The activity of gap junctional channels appears to require both the presence of ATP and protein kinase activity to counteract the tonic activity of endogenous phosphatase(s).  (+info)

Properties of fast endocytosis at hippocampal synapses. (7/8892)

Regulation of synaptic transmission is a widespread means for dynamic alterations in nervous system function. In several cases, this regulation targets vesicular recycling in presynaptic terminals and may result in substantial changes in efficiency of synaptic transmission. Traditionally, experimental accessibility of the synaptic vesicle cycle in central neuronal synapses has been largely limited to the exocytotic side, which can be monitored with electrophysiological responses to neurotransmitter release. Recently, physiological measurements on the endocytotic portion of the cycle have been made possible by the introduction of styryl dyes such as FM1-43 as fluorescent markers for recycling synaptic vesicles. Here we demonstrate the existence of fast endocytosis in hippocampal nerve terminals and derive its kinetics from fluorescence measurements using dyes with varying rates of membrane departitioning. The rapid mode of vesicular retrieval was greatly speeded by exposure to staurosporine or elevated extracellular calcium. The effective time-constant for retrieval can be < 2 seconds under appropriate conditions. Thus, hippocampal synapses capitalize on efficient mechanisms for endocytosis and their vesicular retrieval is subject to modulatory control.  (+info)

Effects of eosinophil granule major basic protein on phosphatidylcholine secretion in rat type II pneumocytes. (8/8892)

Eosinophils are involved in inflammatory diseases such as asthma. We previously reported that activated eosinophils increased the phosphatidylcholine (PC) secretion in primary cultures of rat type II pneumocytes. Increased PC secretion was confirmed to be partly mediated by superoxide anions released from activated eosinophils. However, the influence of eosinophil granule proteins on PC secretion is unknown at present. In this study, we determined whether eosinophil major basic protein (MBP) influences PC secretion. MBP dose dependently increased the PC secretion in rat type II pneumocytes without producing any cell damage. The MBP-induced increase in PC secretion was significantly reduced by preadministration of either H-7, a protein kinase inhibitor, or 1, 2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-AM, a chelator of intracellular Ca2+, but not by H-89, a protein kinase inhibitor. Our results suggest that the MBP-induced increase in PC secretion may provide mechanical stability and protect against lung atelectasis.  (+info)

Background Circumventricular organs (CVO) are cerebral areas with imperfect endothelial blood-brain barrier (BBB) and for that reason thought to be gates to the mind. program. Subsequently, the cells distribution of fluorescence-labeled Gf aswell as the degree of cellular swelling was evaluated in related histological slices. Results We could show that the Gf signal intensity of the choroid plexus, the subfornicular organ and the area postrema increased significantly during experimental autoimmune encephalomyelitis, correlating with (1) disease severity and (2) the delay Dapagliflozin small molecule kinase inhibitor of disease onset after immunization. For the choroid plexus, the extent of Gf enhancement served as a diagnostic criterion to distinguish between diseased and healthy control mice with a sensitivity of 89% and a specificity of 80%. Furthermore, Gf improved the detection of lesions, being particularly sensitive to optic neuritis. In correlated histological slices, Gf initially ...
Neurite outgrowth and neuronal differentiation play a crucial role in the development of the nervous system. subtype (ER) agonist high-throughput drug screening process (Chen et al. 2006). Brann et al. (2007) reported that estrogen receptor modulators may have multi-targeting neuroprotection. Although several studies defined numerous pharmacological effects of liquiritin and its derivatives, neuroprotection and neurotrophic effects in neuronal cells has not been investigated in detail. Thus, we investigated the Sirolimus small molecule kinase inhibitor effects of liquiritin flavonoids in outgrowth of Personal computer12 cells. We noticed significantly enhanced NGF dependent neurite outgrowth in Personal computer12 cells after liquiritin exposure. Furthermore, we discovered overexpression of neural related genes such as for example neurogenin (Nerog) 3, neurofibromatosis (Nf) 1, notch gene homolog (Notch) 2, Sirolimus small molecule kinase inhibitor neuromedin U receptor (Nmur) 2 and neurotrophin ...
Severe food limitation (FR) impairs cardiac performance, even though causative mechanisms remain elusive. Cardiac morphometry was substantially altered, as heart weights were nearly twofold lower in FR rats. Papillary muscle tissue isolated from FR hearts displayed mechanical dysfunction, including reduced created stress and decreased relaxation and contractility. The administration of the SERCA2a blocker resulted in additional decrements in contractile function in FR hearts, recommending impaired SERCA2a activity. Furthermore, the FR rats provided a lower appearance ABT-737 small molecule kinase inhibitor of L-type Ca2+ stations. As a result, myocardial dysfunction induced by serious food restriction is certainly connected ABT-737 small molecule kinase inhibitor with adjustments in the calcium-handling properties in rats. 0.05. 3. Outcomes 3.1. Physical Features Severe food limitation (FR) led to substantial adjustments towards the physical phenotype from the rats. As proven in Desk 1, 3 months ...
Irisin is a novel hormone like polypeptide that is cleaved and secreted by an unknown protease from fibronectin type III domain-containing protein 5 (FNDC5), a membrane- spanning protein and which is highly expressed in skeletal muscle mass, heart, adipose cells, and liver. sending the transmission to determine the function of specific cells, like skeletal muscle mass, liver, pancreas, heart, fat and the brain. The action of irisin on different targeted cells or organs in human being has exposed its physiological functions for promoting health or executing the rules of selection of metabolic illnesses. Numerous studies MLN8237 small molecule kinase inhibitor concentrate on the association of irisin with metabolic illnesses which has obtained great interest being a potential brand-new target to fight type 2 diabetes MLN8237 small molecule kinase inhibitor mellitus and insulin level of resistance. Irisin is available to boost insulin level of resistance and type 2 diabetes by raising sensitization ...
Supplementary MaterialsSupplementary material 1 (DOCX 178?kb) 13205_2019_2000_MOESM1_ESM. positioned at the terminal loop of the hairpin structures, (3) mature miRNAs MLN8054 small molecule kinase inhibitor should have fewer than nine mismatches with the opposite miRNA*sequence, and (4) the predicted secondary structures must have low MFE and high MFEI values, since it is required for distinguishing the miRNAs from other RNAs molecules (MFEIs of tRNAs, rRNAs or mRNAs candidates are 0.64, 0.59 and 0.62C0.66, respectively) (Zhang et al. 2006a). The MFE or G (?kcal/mol) values generated from your MFOLD web server of the stem-loop structures were utilized for calculating the MFEI values using the following formula: length of mature miRNAs, length of precursor Open in a separate windows Fig.?1 Secondary stem-loop structures of the predicted passion fruit miRNA precursors/pre-miRNAs. Respective miRNAs are MLN8054 small molecule kinase inhibitor represented with reddish font Open in a separate windows ...
The unicellular green alga is becoming an invaluable super model tiffany livingston system in plant biology. presented into our algal appearance strains bring about recombinant protein deposition degrees of up to 0.25?% of the full total cellular protein. Furthermore, in ...
The Ras/MEK/ERK and PI3K/Akt/mTor pathways play a central role in the regulation of normal cell growth, division and differentiation. Dysregulation of these signaling pathways driven by oncogenic mutations/activation leading to elevated kinase activity has been demonstrated in many human cancers. Strong evidence suggests the existence of a feedback loop with crosstalk between these two signaling cascades leading to redundancy in survival pathways. Consequently, monotherapy targeting a single cascade may be insufficient to induce tumor cell death due to drug resistance mechanisms. Initial biological results are presented from a series of novel small molecule kinase inhibitors specifically designed to simultaneously target both MEK1 and PI3K. Structural analogs of the ATP-competitive PI3K inhibitor ZSTK474 and the ATP-noncompetitive class of MEK inhibitors PD0325901, respectively, were covalently combined to provide single compound dual inhibitors. Inhibitors showed potent MEK1 inhibition (0.015 , ...
ROS1 is a receptor tyrosine kinase (encoded by the gene ROS1) with structural similarity to the anaplastic lymphoma kinase (ALK) protein; it is encoded by the c-ros oncogene and was first identified in 1986.[7][8][9][10] The exact role of the ROS1 protein in normal development, as well as its normal physiologic ligand, have not been defined.[8] Nonetheless, as gene rearrangement events involving ROS1 have been described in lung and other cancers, and since such tumors have been found to be remarkably responsive to small molecule tyrosine kinase inhibitors, interest in identifying ROS1 rearrangements as a therapeutic target in cancer has been increasing.[7][11] Recently, the small molecule tyrosine kinase inhibitor, crizotinib, was approved for the treatment of patients with metastatic NSCLC whose tumors are ROS1 -positive.[12]. Gene rearrangements involving the ROS1 gene were first detected in glioblastoma tumors and cell lines.[13][14] In 2007 a ROS1 rearrangement was identified in a cell line ...
For glioblastoma (GBM) treatments to be effective in vivo, understanding the effects of the tumor microenvironment is imperative. In traditional cell culture conditions, glucose concentrations do not model physiologic levels, nor the diminished concentrations found in tumor niches. We therefore sought to profile the differences in kinase activity in GBM cells cultured in restricted glucose to identify pathways that could be targeted with small molecule inhibitors. Using the PamStation12 platform, we examined the ability of GBM lysates from cells cultured in standard or low glucose conditions to phosphorylate 144 tyrosine and 144 serine/threonine peptides that correspond to known protein phosphorylation sites. Potential kinase targets were identified and validated using small molecule kinase inhibitors in GBM spheroid cultures. Using results from two GBM patient-derived xenografts, we determined common changes to peptides derived from Phospholipase C, Gamma 1 (PLCG1) and Raf-1. Using PLC and Raf
Imatinib is a small molecule kinase inhibitor used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec (USA) or Glivec (Europe/Australia) as its mesylate salt, imatinib mesilate (INN). It is occasionally referred to as CGP57148B or STI571 (especially in older publications). It is used in treating chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies. It is the first member of a new class of agents that act by inhibiting particular tyrosine kinase enzymes, instead of non-specifically inhibiting rapidly dividing cells ...
ENMD-2076 is a novel orally-active, small molecule kinase inhibitor with a mechanism of action involving several pathways key to tumor growth and survival: angiogenesis, proliferation and the cell cycle. ENMD-2076 has selective activity against the mitotic kinase Aurora A, as well as kinases involved in angiogenesis (VEGFRs, FGFRs). ENMD-2076 inhibited the growth in vitro of a wide range of human solid tumor and hematopoietic cancer cell lines with IC50 values ranging from 0.025-0.7 µM. ENMD-2076 was also shown to induce regression or complete inhibition of tumor growth in vivo, at well-tolerated doses in tumor xenograft models derived from breast, colon, melanoma, leukemia and multiple myeloma cell lines. Pharmacodynamic experiments in vivo demonstrated that in addition to inhibiting Aurora A, single doses of ENMD-2076 had sustained inhibitory effects on the activation of Flt3 as well as the angiogenic tyrosine kinases VEGFR2/KDR and FGFR1 and 2. ENMD-2076 was shown to prevent the formation of ...
The paradoxical role of reactive oxygen species in cell death versus cell survival establishes a delicate balance between chemotherapy efficacy and management of detrimental unwanted effects. cell loss of life in response to both Taxol and cisplatin. We propose that inhibiting the upregulated growth factor-dependent signaling in malignancy cells will target chemo-insensitivity, potentially lowering the necessary dose of the drugs and preventing harmful side effects. strong class=kwd-title Keywords: Lysophosphatidic acid (LPA), Ovarian malignancy, Reactive oxygen varieties (ROS), Chemotherapy, Taxol, Cisplatin Graphical abstract Rabbit Polyclonal to ADAM32 Proliferative signaling happens inside a windows that allows signaling molecules to be reversibly oxidized Z-VAD-FMK small molecule kinase inhibitor and reduced. Chemotherapeutic medicines drive cells toward a higher oxidation state, which is necessary for effective malignancy cell death. The relative side-effect is oxidative harm to normal ...
Supplementary MaterialsAdditional file 1: Number S1. integrin 5 followed by WISP1 (10?g/ml) exposure at 4?h. Supernatants collected at 2-h intervals from 4 to 10?h (TIF 2044 kb) 13054_2018_2237_MOESM2_ESM.tif (1.9M) GUID:?605CBBCF-E3A9-4164-8E35-76B0BA1AC75A Additional file 3: Figure S3. MTV raises inflammatory signaling in lungs of mice after CLP. Western blot for triggered (phosphorylated) p-JNK (A), p-p38 (B) and p-Erk (C) MAP kinase manifestation in lung homogenates. Mice receiving the combination of CLP?+?MTV (two-hit model) were compared to mice subjected to CLP only for 18?h or sham operation followed by 6?h of MTV. Six hours of MTV only had no effect on MAP kinase activation but significantly advertised MAP kinase activation in mice previously subjected to PF-04554878 small molecule kinase inhibitor CLP, whereas TLR4 deletion prevented raises in MAPK activation in CLP-treated and CLP?+?MTV-treated mice and blocking WISP1 or integrin 5 also prevented increase in MAP kinase phosphorylation ...
4409 Treatment of tumors with monoclonal antibodies or small molecule kinase inhibitors targeting the EGF receptor family reveal clinical response rates of 10-20% and little progress has been made towards better selection of patients for these agents. Our quantitave assays of HER 1-4 message levels in 100 colorectal carcinomas revealed that mean HER2 and HER3 levels doubled when compared to matched normal mucosa, prompting us to study the effects of inhibition of these receptors in 11 human colorectal cell lines. We used GW572016, a 6-thiazolyquinazoline reversible kinase inhibitor of both EGFR and HER2 as well as OSI774, an anilinoquinazoline derivative which more selectively inhibits EGFR at low doses. Methods: 1- Real-time fluorescent quantitative PCR assays for HER 1-4 mRNA 2- 72 hour growth inhibition using MTS tetrazolium colorimetric assay (Promega) 3- Soft agar growth in 1 and 5uM inhibitor concentration 4- Flow cytometric cell cycle analysis using Propidium Iodide and APO-BRDU (Phoenix) ...
KinomeScout enables target identification and deconvolution of small molecule kinase inhibitors and works with native proteins in their physiological setting.
OncoLink, the Webs first cancer resource,provides comprehensive information on coping with cancer, cancer treatments, cancer research advances, continuing medical education, cancer prevention, and clinical trials
Background Oligomeric and fibrillar aggregates of the amyloid -peptide (A) have been implicated in the pathogenesis of Alzheimers disease (AD). liter of lifestyle. The technique does not depend on a protein-fusion or -tag and therefore does not need a cleavage response. The purified peptides had been seen as a NMR, circular dichroism, SDS-Web page and size exclusion chromatography, and their aggregation propensities had been assessed by thioflavin T fluorescence and electron microscopy. The info coincide with those reported previously for monomeric, generally unstructured A. ZA3 coexpression furthermore permits the recombinant creation of A(1C42) holding the Arctic PX-478 HCl small molecule kinase inhibitor (Electronic22G) mutation, which in turn causes early onset familial Advertisement. A(1C42)Electronic22G is attained in predominantly monomeric type and suitable, electronic.g., for NMR studies. Bottom line The coexpression of an built aggregation-inhibiting binding proteins presents a novel ...
Supplementary Materials [Supplemental Components] E07-12-1217_index. functions mainly because an antihypertrophic element by avoiding HDAC5 nuclear export which up-regulation of YY1 in human being heart failure could be a protecting system against pathological hypertrophy. Intro YY1 can be a ubiquitously indicated transcription factor that is highly conserved across species and is involved in a variety of cellular processes, including the regulation of cardiac disease (Sucharov (1995) and Bushmeyer and Atchison (1998) . Cell Culture and Adenoviral Contamination Neonatal rat cardiac myocytes (NRVMs) were prepared according to the method described in Waspe (1990) . Cells were infected with an adenovirus expressing YY1-GFP and/or HDAC5-FLAG UNC-1999 small molecule kinase inhibitor or with a control adenovirus at a multiplicity of contamination of 7 plaque-forming units/cell. Real-Time Polymerase Chain Reaction (PCR) Total RNA was extracted by TRIzol (Invitrogen). 0.5 g of RNA was reverse ...
Supplementary MaterialsAdditional document 1: Immunochemisty and AP staining of iPSCs. of iPSC-derived hepatocyte spheroids. b Morphology of iPSC-derived hepatocyte spheroids during culture. Addition of Matrigel matrix (1:100 ratio in 25?L of medium) increased spheroid survival rate. c Immunocytochemistry of iPSC-derived hepatocyte spheroids. Albumin and A1AT marker were expressed. Scale bars, 200?m. (JPG 4520 kb) 13287_2018_1100_MOESM3_ESM.jpg (4.4M) GUID:?00A5D614-83AB-4D7D-9BD9-5AB49D0B9537 Data Availability StatementAll data pertaining to this manuscript are included within the article. Abstract Background Methotrexate (MTX) is usually widely used Vistide small molecule kinase inhibitor for the treatment of rheumatoid arthritis (RA). The drug is cost-effective, but sometimes causes hepatotoxicity, requiring a physicians attention. In this scholarly study, we simulated hepatotoxicity by dealing with hepatocytes produced from RA patientCderived induced pluripotent stem cells (RA-iPSCs) with ...
Long term infection of uterine cervix epithelium with individual papillomavirus (HPV) and constitutive expression of viral oncogenes have been recognized as the main cause of the complex molecular changes leading to transformation of cervical epithelial cells. specific miRNAs and to concur to the deregulation of target genes. Viral encoded circE7 has also demonstrated to overexpress E7 oncoprotein thus contributing to cell transformation. Within this review, we summarize current books in the complicated interplay between miRNAs, lncRNAs, and circRNAs and their function in cervical neoplasia. Baricitinib small molecule kinase inhibitor transcription aspect binding sites in regulatory locations, like the TERT promoter series, have been determined in a substantial small fraction of cervical SCC (14). Epigenetic adjustments, including deregulation of microRNA (miRNA), lengthy nonprotein coding RNA (lncRNA) and round RNA (circRNA) amounts, have shown to try out essential jobs in cell change during ...
Supplementary MaterialsSupplementary Materials: Number S1: Sequences of primers utilized for PCR. peptides, KRGILTLKY and SRYWAIRTR, in to the ER with a tat-derived peptide (GRKKRRQRRR)-His6-ubiquitin (THU) automobile. Duloxetine small molecule kinase inhibitor Both peptides derive from the individual nucleoprotein and actin of influenza trojan, respectively. Our outcomes showed that targeted delivery of both HLA-B?27-binding peptides in to the ER may promote the HLA-B?27 folding, reduce the degrees of (B27-HC)2, and suppress the activation from the IL-23/IL-17 axis in response to lipopolysaccharide. Our results can offer a new healing technique in AS. 1. Launch Ankylosing spondylitis (AS) can be an inflammatory disease thats seen as a inflammatory back discomfort and asymmetric peripheral oligoarthritis [1C4]. The introduction of AS is associated with the expression of individual leukocyte antigen-B strongly?27 (HLA-B?27) [5, 6]. A lot more than 90% of AS sufferers exhibit HLA-B?27. HLA-B?27 ...
TY - JOUR. T1 - Cardiovascular toxicity of tyrosine kinase inhibitors. AU - Mouhayar, Elie. AU - Durand, Jean Bernard. AU - Cortes, Jorge. PY - 2013/9/1. Y1 - 2013/9/1. N2 - Introduction: Small-molecule tyrosine kinase inhibitors (TKIs) have revolutionized the management of many malignancies. However, they also have been shown to be associated with a certain degree of cardiovascular side effects that are often reversible. Areas covered: As the number of new TKIs continues to grow, it is expected that clinicians will be facing the challenge of early detection and 10 management of these side effects while balancing the risk-benefit ratios of continuing with life-saving cancer therapy medications. This review will present the current knowledge related to incidence and proposed mechanisms of cardiovascular side effects of TKIs and also discuss treatment recommendations when available Expert opinion: We will present and discuss available data and suggest recommendations related to patient monitoring ...
Mouse monoclonal to BLK Keeping track of Package-8 (CCK-8, Beyotime, China) and regular colony development assays had been utilized to measure cell proliferation. Each test was repeated 3-4 moments. For cell routine analysis, cells had been gathered 48 hrs after transfection with indicated plasmids, stained with propidium iodide (PI, Sigma) and assayed utilizing a Beckman Coulter Movement Cytometer (Fullerton). Man BALB/c nude mice (4~6 weeks old) had been purchased from the pet Research Committee from the Institute of KU-0063794 Biology and Cell Biology (Shanghai, China) and housed in the Shandong College or university School of Medication animal facility regarding to protocols accepted by the Shandong College or university Animal Treatment Committee. HepG2.2.15 cells (1107) were transplanted subcutaneously into nude mice. After achieving a size of 0.5 cm, tumors were injected with plasmid (20g/100l) every fourth day for a complete of 3-4 injections. Tumor size was supervised every other time. ...
Steroid hormones take action in the central and peripheral nervous systems to regulate a variety of functions, including development, cell proliferation, cognition and behavior. al., 1994). PR-A and PR-B appear to have distinct functions in reproductive behavior and physiology (Mulac-Jericevic and Conneely, 2004; Mani et al., 2006). In the classic genomic mechanism of steroid action (Number 1), steroid receptors in the absence of hormone are complexed with several chaperone molecules, including heat shock protein (hsp)90 (Pratt et al., 2004). Upon binding hormone, steroid receptors undergo a conformational switch that allow receptors to dimerize (DeMarzo et al., 1991). These triggered receptor dimers bind directly to specific steroid response elements (SREs) and SRE-like sequences in the promoter regions of target genes (Mangelsdorf et al., 1995). Binding of receptors to DNA raises or decreases gene transcription by altering the pace of recruitment of general transcription factors and ...
The anti-epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab are used to treat RAS wild-type colorectal cancers (CRCs), but their efficacy is limited by the emergence of acquired drug resistance. After EGFR blockade, about 20% of CRCs develop mutations in the EGFR extracellular domain (ECD) that impair antibody binding and are associated with clinical relapse. We hypothesized that EGFR ECD-resistant variants could be targeted by the recently developed oligoclonal antibody MM-151 that binds multiple regions of the EGFR ECD. MM-151 inhibits EGFR signaling and cell growth in preclinical models, including patient-derived cells carrying mutant EGFR. Upon MM-151 treatment, EGFR ECD mutations decline in circulating cell-free tumor DNA (ctDNA) of CRC patients who previously developed resistance to EGFR blockade. These data provide molecular rationale for the clinical use of MM-151 in patients who become resistant to cetuximab or panitumumab as a result of EGFR ECD mutations. ...
Secondary mutations in the tyrosine kinase domain (TKD) remain the most commonly encountered cause of acquired clinical resistance to small-molecule tyrosine kinase inhibitors (TKI) in human cancer (1-4). Recent pharmaceutical efforts have focused on the development of type II kinase inhibitors, which bind to a relatively nonconserved inactive kinase conformation and exploit an allosteric site adjacent to the ATP-binding pocket as a potential means to increase kinase selectivity, although recent data suggest such efforts may be misguided (5). Commonly, kinase domain (KD) mutations effect resistance to type II inhibitors via two mechanisms: (i) substitution of amino acid positions directly involved in binding inhibitor, or (ii) mutation of residues that stabilize the inactive kinase conformation required for binding (6). Type I inhibitors, which bind to the more conserved active kinase conformation, are typically vulnerable only to mutations at inhibitor contact residues and therefore may be ...
Seattle Genetics recently released data suggesting that tucatinib, when combined with trastuzumab (Herceptin; Genentech) and capecitabine, may effectively treat patients with locally advanced inoperable or metastatic HER2-positive breast cancer who have received prior therapies. In a phase II trial, the drug extended overall survival (OS) and progression-free survival (PFS) compared with trastuzumab and capecitabine alone and provided a PFS benefit in patients with brain metastases.. Patients with HER2-positive breast cancer usually receive trastuzumab and pertuzumab (Perjeta; Genentech) plus a taxane-based chemotherapy first, followed by ado-trastuzumab emtansine (T-DM1, Kadcyla; Genentech) for progressive disease. Once the disease metastasizes, however, effective therapies are lacking, especially for the 30% to 50% of patients who also develop brain lesions.. Highly selective for HER2, tucatinib is a small-molecule tyrosine kinase inhibitor (TKI). In a phase Ib trial, tucatinib plus ...
Imatinib mesylate is a small-molecule tyrosine kinase inhibitor that was initially developed as a 2-phenylaminopyrimidine derivative specific for PDGFR. Imatinib was subsequently found to be a potent inhibitor of ABL kinases, including the BCR-ABL fusion protein generated as a result of the t(9;22) chromosomal translocation (Philadelphia chromosome) found in chronic myelogenous leukemia (CML), and was…. ...
Based on genetic studies that establish the role of spleen tyrosine kinase (Syk) in immune function, inhibitors of this kinase are being investigated as therapeutic agents for inflammatory diseases. Because genetic studies eliminate both adapter functions and kinase activity of Syk, it is difficult to delineate the effect of kinase inhibition alone as would be the goal with small-molecule kinase inhibitors. We tested the hypothesis that specific pharmacological inhibition of Syk activity retains the immunomodulatory potential of Syk genetic deficiency. We report here on the discovery of (4-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-2-((1R,2S)-2-aminocyclohexylamino) pyrimidine-5-carboxamide acetate (P505-15), a highly specific and potent inhibitor of purified Syk (IC50 1-2 nM). In human whole blood, P505-15 potently inhibited B cell antigen receptor-mediated B cell signaling and activation (IC50 0.27 and 0.28 μM, respectively) and Fcε receptor 1-mediated basophil degranulation (IC50 0.15 μM). ...
In a phase I trial, the combination of the BCR-ABL1 inhibitor asciminib and the small-molecule kinase inhibitor imatinib showed preliminary efficacy, safety, and tolerability in patients with chronic myeloid leukemia (CML) resistant to or intolerant of treatment with two or more prior tyrosine kinase inhibitors. These data were presented by Talpaz et al at the 2019 Society of Hematologic Oncology (SOHO) Annual Meeting and published in Clinical Lymphoma, Myeloma & Leukemia.. Methods. A total of 25 patients with chronic phase CML were enrolled in the trial; 15 of the 25 had been treated with more than two prior tyrosine kinase inhibitors and 17 of the 25 had previously been treated with imatinib. Asciminib was administered in continuous 28-day cycles at 40 mg (n = 9), 60 mg (n = 6), or 80 mg (n = 4) once a day or 40 mg twice a day (n = 6) plus imatinib at 400 mg once a day (n = 6).. Efficacy. At data cutoff, treatment was ongoing in 17 patients. Four patients had discontinued treatment due to ...
Small-molecule kinase inhibitors are predominantly discovered in pure protein assays. We have discovered an inhibitor of Rho-kinase (ROCK) through an image-based, high-throughput screen of cell monolayer wound healing. Using automated microscopy, we screened a library of approximately 16,000 compoun …
Back ground: Insulin-like growth factor-1 receptor (IGF1R) activity is upregulated in a variety of human cancers and IGF1R signaling has been implicated as a mechanism of resistance to various cancer therapies, including radiotherapy, cytotoxic chemotherapy, and targeted molecular therapy. We have demonstrated that IGF1R activation can induce resistance to targeted therapy of head and neck squamous cell carcinomas (HNSCCs) using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Targeting the IGF1R by selective small molecule kinase inhibition may thus hold promise as an adjuvant treatment for HNSCC.. Aims: (1) To assess the anti-tumor effects of two IGF1R/insulin receptor TKIs, BMS-754807 and OSI-906, in multiple HNSCC cell lines in vitro. (2) To evaluate the effect of combined IGF1R and EGFR inhibition in HNSCC cell lines in vitro.. Methods: The effect of IGF1R inhibition on cell proliferation, viability, survival, and apoptosis was assessed using alamarBlue, trypan ...
Exquisitely selective turn-on probes of kinase activation and localization Protein kinase-mediated phosphorylation is a vital posttranslational modification in eukaryotic cell signaling. Efforts to understand these complex signaling pathways have been hampered by a lack of selective kinase inhibitors. Nearly all known kinase inhibitors bind in the highly conserved ATP pocket. Although potency is easy to obtain within the ATP-pocket, selectivity is difficult to obtain due to the similar nature of this binding pocket across the kinome. Non-ATP-competitive inhibitors usually possess higher degrees of selectivity than their ATP-competitive counterparts, however, they generally suffer from a lack of potency. In contrast, both high potency and high selectivity can be obtained with bisubstrate inhibitors. Bisubstrate kinase inhibitors interact with both binding pockets; interactions within the ATP pocket provide potency while interactions within the substrate site provide selectivity. Here, we propose ...
The test is intended to be used to identify patients with advanced NSCLC whose tumors harbor mutations in exons 18, 19, 20 and 21 of the EGFR gene, and to select patients for treatment with small molecule tyrosine kinase inhibitors (TKIs) that target EGFR, and where the sample tumour content is low (i.e. less 30%). Sanger sequencing is currently still the method of choice for samples with tumour content of 30% or higher. ...
Most potent protein kinase inhibitors act by competing with ATP to block the phosphotransferase activity of their targets. families encoded by the human genome and major constituents of most intracellular signaling cascades (Manning et al., 2002b),(Manning et al., 2002a). These signaling enzymes play important functions in countless cellular pathways, and the proper regulation of their activity is essential for normal cellular behavior. Aberrant kinase function is usually linked to numerous diseases, and a number of kinases are promising targets for the development of small molecule-based therapies (Cohen and Alessi, 2013). Currently, Ehk1-L a majority of potent and selective kinase inhibitors block phosphotransferase activity by competing with ATP (Zhang et al., 2009). While many of these inhibitors are able to interact with the ATP-binding clefts of kinases in an active conformation, a subset of inhibitors are conformation-selective, in that they only bind to their targets if conserved ...
Chromosomal rearrangements that lead to oncogenic kinase activation are observed in many epithelial cancers. These cancers express activated fusion kinases that drive the initiation and progression of malignancy, and often have a considerable response to small-molecule kinase inhibitors, which valid …
The advent of Gleevec® (imatinib) less than 10 years ago was a landmark for utilizing small molecule compounds as kinase inhibitor drugs (1-3). This type of drug is usually directed against one specific kinase whose malfunctioning plays a key role in the given disease. Generally these drugs are thought to be selective, easy to modify, and effective. As the molecular principles of various diseases are better understood, kinase inhibitors are being developed in various fields with cancer remaining the predominant one (4). Kinase inhibitor compounds constitute about 30% of all drug development programs in the pharmaceutical industry (5).. Kinase inhibitor drugs are typically developed with a targeted and rational strategy, often focusing on a kinase known to be involved in the etiology of a disease. Large libraries of chemical compounds, for example ATP analogs, are screened in vitro against the activity of this kinase, and their effects on a panel of manually selected kinases with similar ...
Siragen Pharmaceuticals, a spin-off from NeuroGeneration, is developing small-molecule kinase inhibitors for the treatment of prostate and hepatic cancers.
Treatment with epidermal development aspect receptor tyrosine kinase inhibitors (EGFR-TKIs), such as for example gefitinib and erlotinib, offers achieved great clinical response prices in sufferers with nonCsmall cell lung malignancies (NSCLCs). without them [1 of 7 (14%) vs 9 of 15 (60%); chi-squared check, p ?=? 0.0449], indicating the harmful correlation between your immune system responses towards the EGFR-T790M-derived epitopes and the current presence of EGFR-T790M mutation in NSCLC sufferers. This finding may be explained with the hypothesis that immune system responses towards the mutated neo-antigens produced Docetaxel (Taxotere) from T790M might avoid the introduction of tumor cell variations using the T790M Docetaxel (Taxotere) level of resistance mutation in NSCLC sufferers during EGFR-TKI treatment. Jointly, our results claim that the discovered T cell epitopes may provide a book immunotherapeutic strategy for avoidance and/or treatment of EGFR-TKI level of resistance with the ...
1qpc: Structural analysis of the lymphocyte-specific kinase Lck in complex with non-selective and Src family selective kinase inhibitors.
1qpc: Structural analysis of the lymphocyte-specific kinase Lck in complex with non-selective and Src family selective kinase inhibitors.
DESCRIPTION (provided by applicant): Hematologic toxicity is a principal cause of morbidity and mortality after exposure to ionizing radiation (IR). G-Zero Therapeutics, with operations in the Research Triangle Park, North Carolina, has developed a novel approach to mitigating the hematologic toxicity of total body irradiation (TBI). This approach relies on the administration of novel, orally bioavailable small molecule kinase inhibitors around the time of exposure to TBI. These compounds in turn induce pharmacological quiescence (PQ) of the early hematopoietic stem and progenitor cells (HSPC) through the inhibition of cyclin dependent kinases (CDKs) which govern the G1-S transition of the cell cycle. As quiescent cells are resistant to IR, PQ enhances the per cell survival of HSPC by augmenting the repair of DNA damage post-TBI. This enhanced survival of HSPC in turn translates into markedly reduced acute hematologic toxicity. G-Zero has shown in mice that the PQ approach can significantly ...
Supplementary MaterialsData_Sheet_1. addition, in severe midbrain pieces of man Sprague-Dawley rats, we discovered that 6-OHDA decreased the spike rheobase and variety of DA neurons, that have been PA-824 small molecule kinase inhibitor also reversed by pretreatment with 4-PBA and ryanodine. TUNEL staining and MTT assays also showed that 4-PBA and ryanodine obviously alleviated 6-OHDA-induced cell apoptosis and devitalization. Interestingly, a IP3Rs blocker experienced little effect on the above 6-OHDA-induced neurotoxicity in DA neurons. In conclusion, our findings provide evidence of the different tasks of IP3Rs and RyRs in the rules of endogenous Ca2+ homeostasis, neuronal excitability, and viability in DA neurons, and suggest a potential therapeutic strategy for PD by inhibiting the RyRs Ca2+ channels in the ER. model system for study SNc DA neurons (Son et al., 1999). We also investigated cellular excitability in a 6-OHDA-induced PD model in midbrain slices. Our data demonstrated the ...
Olfactory ensheathing cells (OECs) are a type of specialized glial cell currently considered as having a double function in the nervous system: one regenerative, and another immune. OEC cultures resulted in continuous NF-B activation. The IFN-induced increase of iNOS manifestation was reversed in infected OECs. OECs are susceptible to infection, which can suppress their cytotoxic mechanisms in order to survive. We suggest that, in contrast to microglia, OECs might serve as safe focuses on for pneumococci, providing a more stable environment for evasion of the immune system. Olfactory ensheathing cells (OECs) are a type of specialized glial cell that accompany and ensheath the primary olfactory axons through the olfactory pathway, from your olfactory epithelium to Natamycin small molecule kinase inhibitor the olfactory tract. OECs are crucial for olfactory axonal assistance and outgrowth inside the developing and adult olfactory program1,2. This real estate of OECs makes them a superb candidate ...
TY - CHAP. T1 - Targeted Therapies in Chronic Myeloid Leukemia. AU - Jabbour, Elias. AU - Cortes, Jorge. PY - 2015/10/30. Y1 - 2015/10/30. N2 - Until 2000, therapy for chronic myeloid leukemia (CML) was limited to nonspecific agents such as busulfan, hydroxyurea, and interferon-alpha (IFN-a). The landscape changed dramatically with the development of small-molecule tyrosine kinase inhibitors (TKIs) that was shown to potently interfere with the interaction between the BCR-ABL protein and adenosine triphosphate (ATP), blocking cellular proliferation of the malignant clone. Three TKIs are commercially available for the front-line treatment of CML: imatinib, dasatinib, and nilotinib. With the updates of the DASISION and ENESTnd trials, the question often arises as to the optimal choice for front-line management of CP-CML. Based on attainment of faster and higher rates of complete cytogenetic response (CCyR), major molecular response (MMR), and complete molecular response (CMR), and a trend for lower ...
Relapse occurred in 7 (44%) of the 16 patients who stopped tyrosine kinase inhibitor treatment at the time of complete remission, 4 (33%) of the 12 who stopped treatment after additional cycles, and 1 (13%) of the 8 who were still receiving a tyrosine kinase inhibitor. The median time from complete remission to relapse was 7.9 months (range, 3-32 months). Relapse occurred at a previously involved metastatic site in 5 of 12 patients with relapse. Thus, of the 28 patients who stopped tyrosine kinase inhibitor treatment, 17 (61%) remained in complete remission after a median follow-up of 8.5 months (range, 0.3-39.1 months). Tyrosine Kinase Inhibitor Plus Local Treatment. A total of 28 patients (44%) achieved complete remission with a tyrosine kinase inhibitor and local therapy (Fig. 2), consisting of surgery in 22 (79%), radiofrequency ablation in 2 (7%), and radiation therapy in 4 (14%). Most patients received local therapy for pulmonary metastases. The median time from starting tyrosine kinase ...
AZD-0424 is an orally bioavailable small molecule tyrosine kinase inhibitor that targets both Abl and Src kinases with potential antineoplastic activity. Upon oral administration, AZD0424 selectively inhibits both Src and Abl kinase activity which may result in the inhibition of tumor growth in susceptible tumor cells. Src and Abl kinases are upregulated in certain tumor cells and play important roles in tumor cell proliferation and metastasis. Check for active clinical trials or closed clinical trials using this agent.
The transforming growth factor α (TGFα) epidermal growth factor receptor (EGFR) autocrine pathway plays a key role in the development and progression of human epithelial cancers (1). Overexpression of TGFα and/or EGFR has been detected in the majority of human carcinomas, has been associated with resistance to cytotoxic drugs and to hormone therapy, and is generally an indicator of poor prognosis (1). For these reasons, the blockade of the EGFR-driven autocrine pathway has been proposed as a target for anticancer therapy (2). Several pharmacologic approaches have been developed for blocking EGFR. The two most successful approaches for the treatment of cancer patients have been thus far the anti-EGFR-blocking monoclonal antibodies (MAb), such as Cetuximab, and the selective EGFR small molecule tyrosine kinase inhibitors (TKI), such as Gefitinib and Erlotinib (3-5).. Tumor angiogenesis is the process leading to the formation of blood vessels within a tumor and plays a key role in cancer cell ...
HER2/ERBB2-overexpressing breast cancers targeted effectively by the small-molecule kinase inhibitor lapatinib frequently acquire resistance to this drug. In this study, we employed explorative mass spectrometry to profile proteome, kinome, and phosphoproteome changes in an established model of lapatinib resistance to systematically investigate initial inhibitor response and subsequent reprogramming in resistance. The resulting dataset, which collectively contains quantitative data for ,7,800 proteins, ,300 protein kinases, and ,15,000 phosphopeptides, enabled deep insight into signaling recovery and molecular reprogramming upon resistance. Our data-driven approach confirmed previously described mechanisms of resistance (e.g., AXL overexpression and PIK3 reactivation), revealed novel pharmacologically actionable targets, and confirmed the expectation of significant heterogeneity in molecular resistance drivers inducing distinct phenotypic changes. Furthermore, our approach identified an ...
We have developed a deep generative model, generative tensorial reinforcement learning (GENTRL), for de novo small-molecule design. GENTRL optimizes synthetic feasibility, novelty, and biological activity. We used GENTRL to discover potent inhibitors of discoidin domain receptor 1 (DDR1), a kinase target implicated in fibrosis and other diseases, in 21 days. Four compounds were active in biochemical assays, and two were validated in cell-based assays. One lead candidate was tested and demonstrated favorable pharmacokinetics in mice. A machine learning model allows the identification of new small-molecule kinase inhibitors in days.
By Kevin E. Noonan -- Lest anyone think that Myriad Genetics is the only patentee asserting rights in patents having claims to isolated DNA molecules or other biological molecules, St. Judes Childrens Research Hospital, Inc. has sued Novartis Pharmaceuticals Corp. in the Federal District Court, Western District of Tennessee for infringing U.S. Patent Nos. 5,529,925; 5,770,421; and 6,696,548 (see Court Report, October 20, 2013). The grounds for St. Judes infringement allegations are activities by Novartis to research, develop, and evaluate small molecule tyrosine kinase inhibitors, including, but not limited to, LDK378, some of that research having taken place in Memphis,...
Knockdown or genetic deletion of PTEN promotes substantial axon regeneration in an mTOR-dependent manner, both in the optic nerve and in the CST (Park et al., 2008, 2010; K. Liu et al., 2010; Zukor et al., 2013; Du et al., 2015). It has therefore been suggested that the activity of S6K1, an effector of mTOR, is required for regeneration in this paradigm (Yang et al., 2014). Nevertheless, experimental results on this point are conflicting (Hubert et al., 2014; Yang et al., 2014). In our study, we found that decreased phosphorylation of S6K1s substrate, S6, strongly correlates with promotion of neurite outgrowth in primary neurons treated with a variety of small-molecule kinase inhibitors, and that pharmacological inhibition of S6K1 promotes neurite outgrowth in primary neurons. Activation of PI3K/mTOR signaling, in response to the release of S6K1-mediated negative feedback on this pathway, may be driving the induction of neurite outgrowth. Consistent with this, we observed that inhibiting S6K1 ...
Enterotoxigenic (ETEC) diarrheal disease is a worldwide problem that may be addressed by transcutaneous delivery of a vaccine. also be achieved by intravenous injection of the immune sera. Finally, a malaria vaccine antigen, merzoite surface protein 142 administered with CT as the adjuvant, induced both merzoite surface protein antibodies and T-cell responses while conferring protective antitoxin immunity, suggesting that both antiparasitic activity and antidiarrheal activity can be obtained with a single vaccine formulation. Overall, our results demonstrate that relevant colonization factor and antitoxin immunity can be induced by TCI and suggest that an ETEC travelers diarrhea vaccine could be delivered by using a patch. Enterotoxigenic (ETEC) diarrhea is a worldwide problem that is responsible for 400,000 to 800,000 deaths per year (20). It is a primary cause of morbidity and mortality in children less than 5 years old (3, 39) and is a significant cause of Linagliptin small molecule kinase ...
The subject has received non-standard radiation therapy for glioblastoma, non-anti-angiogenic therapy (including investigational agents, small-molecule kinase inhibitors, and biologic agents) or non-cytotoxic hormonal agent within 28 days of the first scheduled dose of XL184 or mitomycin C within 42 days of the first scheduled dose of XL184, other investigational therapy (including agents not specified above) within 28 days of the first scheduled dose of XL184, or prior treatment with nitrosoureas (including carmustine wafer) at any time ...
The cortistatins are a group of steroidal alkaloids first isolated in 2006 from the marine sponge Corticium simplex. The cortistatins were first discovered in a search for naturally occurring compounds that inhibit proliferation of human umbilical vein endothelial cells (HUVECs), with cortistatin A being the most potent compound in the class. The Shair group at Harvard along with collaborators have shown that cortistatin A is a highly potent and selective inhibitor of CDK8 and CDK19, the kinases that associate with Mediator complex. Out of 386 kinases evaluated, cortistatin A only inhibited CDK8 and CDK19, revealing that it is among the most selective kinase inhibitors. It was also shown that cortistatin A potently inhibits growth of acute myeloid leukemia cells and AML in two in vivo mouse models. Identification of dominant drug-resistant alleles of CDK8 and CDK19 demonstrate that these kinases mediate the activity of cortistatin A in AML cells. Thus, inhibition of CDK8 and CDK19 is a new ...
Background Several little receptor tyrosine kinase inhibitors (RTKI) have entered medical cancer trials alone and in conjunction with radiotherapy or chemotherapy. cells had been employed. LEADS TO fibroblasts, rays markedly triggered PDGF signaling as recognized by improved PDGFR phosphorylation that was potently inhibited by SU9518. In fibroblast clonogenic assay, SU9518 decreased PDGF activated fibroblast success by 57%. Also, SU9518 potently inhibited fibroblast and endothelial cell proliferation. In the co-culture model, rays of endothelial cells and fibroblast cells considerably activated proliferation of non irradiated fibroblasts and vice versa. Significantly, the RTK inhibitor considerably inhibited this paracrine buy 838818-26-1 radiation-induced fibroblast and endothelial cell activation. Summary Radiation-induced autocrine and paracrine PDGF signaling takes on an important part in fibroblast and endothelial cell proliferation. SU9518, a PDGFR tyrosine kinase inhibitor, decreases ...
TY - JOUR. T1 - An EGFR signature predicts cell line and patient sensitivity to multiple tyrosine kinase inhibitors. AU - Cheng, Chao. AU - Zhao, Yanding. AU - Schaafsma, Evelien. AU - Weng, Yi Lan. AU - Amos, Christopher. PY - 2020/11/1. Y1 - 2020/11/1. N2 - EGFR is an oncogene with a high frequency of activating mutations in nonsmall cell lung cancer (NSCLC). EGFR inhibitors have been FDA-approved for NSCLC and have shown efficacy in patients with certain EGFR mutations. However, only 9% to 26% of these patients achieve objective responses. In our study, we developed an EGFR gene signature based on The Cancer Genome Atlas (TCGA) RNA-seq data of lung adenocarcinoma (LUAD) to direct the preselection of patients for more effective EGFR-targeted therapy. This signature infers baseline EGFR signaling pathway activity (denoted as EGFR score) in tumor samples, which is associated with tumor sensitivity to EGFR inhibitors and other tyrosine kinase inhibitors (TKIs). EGFR score predicted sensitivity of ...
Background: Tyrosine kinase inhibitors (TKIs) have increased survival dramatically for patients with chronic myeloid leukemia (CML), but continuous administration of these drugs may elicit long-term toxicity. Objective: To investigate the incidence of vascular events in patients with CML treated with first-and second-generation TKIs. Design: Retrospective cohort study using nationwide population-based registries. Setting: Sweden. Patients: All patients diagnosed with chronic-phase CML in Sweden from 2002 to 2012 and treated with a TKI, and 5 age- and sex-matched control individuals per patient. Measurements: Relative risks, expressed as incidence rate ratios comparing patients with control individuals, were calculated. Events per 1000 person-years were assessed in interdrug comparisons. Results: 896 patients, 94.4% with documented TKI treatment, were followed for a median of 4.2 years. There were 54 arterial and 20 venous events in the CML cohort, corresponding to relative risks of 1.5 (95% CI, ...
Orally bioavailable compounds that target key intracellular signalling molecules are receiving increasing attention for the treatment of rheumatic diseases. The mitogen activated protein (MAP) kinases are especially attractive because they regulate both cytokine production and cytokine action. The MAP kinases are expressed and activated in rheumatoid arthritis (RA) synovium. Preclinical studies using MAP kinase inhibitors are very effective in animal models of arthritis, supporting their potential utility in human disease. Although the available data suggest a rationale for MAP kinase blockade, development of drugs has been hampered by toxicity and limited efficacy. Alternative strategies, such as targeting other kinases in the cascade or development of allosteric inhibitors have been proposed. These approaches might permit effective use of MAP kinase inhibitors for the treatment of rheumatic and immune-mediated diseases.. ...
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Purpose : Protein kinases play an important role in several cell processes such as proliferation, transcription, and pathologic changes. Kinase inhibitors have thus been proposed for treatment against diseases including cancer. In ophthalmology, ROCK inhibitor has already been launched as an antiglaucoma drug in Japan. However, discovery of small molecule inhibitors for specific protein kinases is still challenging. This is because approximately 500 protein kinases exist and more than 2,000 other purine-binding proteins share similar ATP binding pockets of kinases. The purpose of this study was to develop an in silico method for identifying potential kinase inhibitors, and the anticancer drug axitinib was used as a representative kinase inhibitor. Methods : Sequences for 9 typical kinases were compared to VEGFR tyrosine kinase, the three amino acid sequences on the hinge region of each kinase were identified, and the surfaces of the ATP binding cavities in the kinases were analyzed in silico ...
Introduction: Kinase inhibitors have been hailed as a breakthrough in the treatment of cancer. Extensive research is now being devoted to the development of kinase inhibitors as a treatment for many nonmalignant diseases. However, the use of kinase inhibitors in both malignant and nonmalignant diseases is also associated with side effects and the development of resistance. It may be worthwhile to explore whether cell-specific delivery of kinase inhibitors improves therapeutic efficacy and reduces side effects.. Areas covered: This review aims to provide an overview of the preclinical studies performed to examine the specific targeting of kinase inhibitors in vitro and in vivo. It gives an introduction to kinase signaling pathways induced during disease, along with the possible problems associated with their inhibition. It also discusses the studies on specific delivery and shows that altering the specificity of kinase inhibitors by targeting methods improves their effectivity and safety.. Expert ...
TY - JOUR. T1 - Acquired platelet antagonism: off-target antiplatelet effects of malignancy treatment with tyrosine kinase inhibitors. AU - Tullemans, B. M. E.. AU - Heemskerk, J. W. M.. AU - Kuijpers, M. J. E.. PY - 2018/9/1. Y1 - 2018/9/1. KW - cancer. KW - platelets. KW - signaling. KW - therapy. KW - tyrosine kinase inhibitor. KW - CHRONIC MYELOID-LEUKEMIA. KW - CELL LUNG-CANCER. KW - CHRONIC LYMPHOCYTIC-LEUKEMIA. KW - ENDOTHELIAL GROWTH-FACTOR. KW - FACTOR RECEPTOR INHIBITOR. KW - BCR-ABL INHIBITOR. KW - PHASE-2 TRIAL. KW - DOUBLE-BLIND. KW - OPEN-LABEL. KW - ANGIOGENESIS INHIBITORS. U2 - 10.1111/jth.14225. DO - 10.1111/jth.14225. M3 - Review article. C2 - 29975003. VL - 16. SP - 1686. EP - 1699. JO - Journal of Thrombosis and Haemostasis. JF - Journal of Thrombosis and Haemostasis. SN - 1538-7933. IS - 9. ER - ...
Background: Tyrosine kinase inhibitor (TKI)-based therapy is a recommended treatment for patients with chronic myeloid leukemia (CML). However, a considerable group of CML patients do not respond well to the TKI therapy. Challenging to overcome this problem, we tried to discover molecular signatures in gene expression profiles to discriminate the responders and non-responders of TKI therapy. Methods: We collected three microarray datasets of CML patients having total 73 responders and 38 non-responders. Statistical analysis was performed to identify differentially expressed genes (DEGs) as gene signature candidates from integrated microarray datasets. The classification performance of these genes and further selected discriminator gene sets was tested by using random forest and iterative backward variable selection methods. Results: We identified a set of genes including CTBP2, NADK, AZU1, CTSH, FSTL1, and HDLBP showing the highest accuracy more than 69.44 % to classify TKI response in CML ...
Supplementary test information for BCR-ABL1 Mutation Analysis for Tyrosine Kinase Inhibitor Resistance such as test interpretation, additional tests to consider, and other technical data.
Demetri, GD SEMINARS IN ONCOLOGY APR 2011″ During the previous ten years, tyrosine kinase inhibitors (TKIs) have revolutionized the remedy of gastrointestinal stromal tumors (GIST), supplying new treatment choices with unprecedented medical benefit. Recognition with the key function played by … Continue reading →. ...
PIM1/2 Kinase Inhibitor VI - CAS 587852-28-6 - Calbiochem The PIM1/2 Kinase Inhibitor VI, also referenced under CAS 587852-28-6, controls the biological activity of PIM1/2. This small molecule/inhibitor is primarily used for Phosphorylation & Dephosphorylation applications. - Find MSDS or SDS, a COA, data sheets and more information.
Tandospirone(SM-3997) is a potent and selective 5-HT1A receptor partial agonist (Ki = 27 nM) that displays selectivity over SR-2, SR-1C, α1, α2, D1 and D2 receptors (Ki values ranging from 1300-41000 nM ...
Proteases Inhibitors on signaling pathway are available at Adooq Bioscience. Check Proteases pathway , inhibitors reviews and assay information.
Struc tural data of HsHDAC8 pointed out the purpose in the residue D101 in the two substrate and HDACi recognition, HsH DAC8D101A mutated enzyme was inactive on protein sub strates and binding efficiency to hydroxamate inhibitor was decreased.Provided that D101 is localized from the vicinity of T99 of TgHDAC3, these data further strengthen the hypoth esis of a direct inhibition of TgHDAC3 by FR235222 and therefore are steady with a function of T99 in the interactions with cy clopeptide inhibitors. T99A and T99I adjust amino acid polarity, its as a result tempting to speculate that polar inter actions on the rim of the lively web page assistance the binding to HDACis, as proposed by Vannini et al.We predict the binding efficiency of HDACis to TgHDAC3 will be diminished while in the T99A and T99I mutated versions of TgH DAC3. On the other hand, an impact of these mutations within the regula tion and or exercise of TgHDAC3 compensating the decrease in HDAC activity triggered by drug inhibition ...
Kyowa Hakko Kirin is developing a series of orally active inhibitors of tyrosine kinases for the treatment of cancer. The rationale for the development of the
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UNC2250 is a potent and selective Mer Kinase inhibitor. When applied to live cells, UNC2250 inhibited steady-state phosphorylation of endogenous Mer with an IC50 of 9.8 nM and blocked ligand-stimulated activation of a chimeric EGFR-Mer protein. Treatment with UNC2250 also resulted in decreased colony-forming potential in rhabdoid and NSCLC tumor cells, thereby demonstrating functional antitumor activity. The results provide a rationale for further investigation of UNC2250 for therapeutic application in patients with cancer..
To meet the increasing global demand for energy we need to innovate new ways to harness and convert renewable energy sources. Solar energy provides a huge potential to meet these demands, but there is still a plethora of ...
Read chapter 62 of Goodman & Gilmans: The Pharmacological Basis of Therapeutics, 12e online now, exclusively on AccessBiomedical Science. AccessBiomedical Science is a subscription-based resource from McGraw Hill that features trusted medical content from the best minds in medicine.
RO9021 is an orally bioavailable, novel ATP-competitive inhibitor of SYK, with an average IC50 of 5.6 nM. - Mechanism of Action & Protocol.
Such a rule, while not completely exhaustive, can serve some valuable purposes. For one thing as the authors demonstrate, it can be used to fish out kinase inhibitor-like molecule hits/leads from a database of existing drugs. This is of course a well-known strategy, to use a drug prescribed for one ailment to treat a different one, and one of the big advantages of this is that because the drug has been on the market its PK/ADME-TOX properties are already well-established. But its not easy to do in general, and its nice to have a structural rule that could weed out such drugs and redeploy them for targeting kinases. In this case, the fished-out drugs that originally bound to totally different targets did show broad-spectrum kinase activity experimentally ...
Arian, R; Hariri, Am; Mehridehnavi, A; Fassihi, A; Ghasemi, F (April 27, 2020). "Protein kinase inhibitors' classification ...
Others examine the composition of protein kinase inhibitors.[24] The most recent patents are specific the methodologies of ... RET inhibitors: Vandetanib (also VEGFR and EGFR). Entrectinib (ALK, ROS1, NTRK). c-MET inhibitor: Cabozantinib (also VEGFR2). ... Ceritinib is an anaplastic lymphoma kinase (ALK)-positive inhibitor primarily used for the treatment of metastatic NSCLC.[4] ... Ceritinib is a selective and potent inhibitor of anaplastic lymphoma kinase (ALK). In normal physiology, ALK functions as a key ...
It shows protein kinase C inhibitor activity. Foeniculoside I is a glucoside of cis-miyabenol C. Mattivi, F.; Vrhovsek, U.; ... "Naturally Occurring Protein Kinase C Inhibitors; II. Isolation of Oligomeric Stilbenes from Caragana sinica". Planta Medica. 61 ...
Experimental medications: sorafenib a combined Tyrosine protein kinases inhibitor. Scheduling of drug treatments and ... kinases. Heparanase cleaves heparin sulfate chains of HSPGs, which have an extensive network with several proteins on the cell ... The ECM protein tenascin C (TNC) is up-regulated in metastatic breast cancer. TNC is an adhesion-modulating extracellular ... Some of these proteins are discussed here in relation to breast-cancer metastasis. Fibronectin is an extracellular glycoprotein ...
Patrick D, Heimbrook D (1996). "Protein kinase inhibitors for the treatment of cancer". Drug Discovery Today. 1 (8): 325-330. ... The compounds were found to inhibit a variety of protein kinases signifying a possible role in cancer treatment. The structure ... betaenone C has been shown to inhibit RNA and protein synthesis. Most of the major work on betaenone B, including the initial ... "Specific inhibitors of eukaryotic DNA synthesis and DNA polymerase alpha, 3-deoxyaphidicolin and aphidicolin-17-monoacetate". ...
Patrick, D.; Heimbrook, D (1996). "Protein kinase inhibitors for the treatment of cancer". Drug Discovery Today. 1: 325-330. ... Novel Inhibitors of Protein Kinases". Journal of Natural Products. 63: 739-745. doi:10.1021/np9905259. PMID 10869191.. ... The compounds were found to inhibit a variety of protein kinases. Betaenone A Betaenone B Betaenone C Two further betaenones ...
... various TPE derivatives like tamoxifen and clomifene have been found to act as protein kinase C inhibitors. The affinity of ... a new class of protein kinase C inhibitors". J. Natl. Cancer Inst. 76 (6): 1243-6. doi:10.1093/jnci/76.6.1243. PMID 3458960. ... The tamoxifen metabolite and aromatase inhibitor norendoxifen is also a TPE derivative. In addition to their estrogenic ...
C16 (PKRi, GW 506033X) is a drug which acts as a selective inhibitor of the enzyme double-stranded RNA-dependent protein kinase ... S-17092 Jammi, NV; Whitby, LR; Beal, PA (Aug 2003). "Small molecule inhibitors of the RNA-dependent protein kinase". ... Shimazawa, M; Hara, H (Dec 2006). "Inhibitor of double stranded RNA-dependent protein kinase protects against cell damage ... "Interaction of double-stranded RNA-dependent protein kinase (PKR) with the death receptor signaling pathway in amyloid beta ( ...
Roskoski, Robert (June 2019). "Properties of FDA-approved small molecule protein kinase inhibitors". Pharmacological Research. ... Structural biology of human proteins - The SGC has so far contributed over 2000 protein structures of human proteins of ... and version 1.0 of 187 chemogenomic inhibitors (aka KCGS) for 215 kinases have been co-developed. Integral membrane proteins ... These families include epigenetic signaling, solute transport, protein proteostasis, and protein phosphorylation. The protein ...
2010). "Extended kinase profile and properties of the protein kinase inhibitor nilotinib". Biochimica et Biophysica Acta (BBA ... See also: Discovery and development of Bcr-Abl tyrosine kinase inhibitors. Nilotinib was developed by Novartis.[3] It was ... Breccia, M.; Alimena, G. (2010). "Nilotinib: a second-generation tyrosine kinase inhibitor for chronic myeloid leukemia". ... "Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors". Drug Metabol Drug Interact. 29 (4): 249-59. doi:10.1515/ ...
2007). "The selectivity of protein kinase inhibitors: a further update". Biochem J. 408 (3): 297-315. doi:10.1042/BJ20070797. ... 2-INDOLINONE PROTEIN TYROSINE KINASE INHIBITORS Blake, R. A., M. A. Broome; et al. (2000). "SU6656, a selective src family ... SU6656 was initially identified as a Src kinase inhibitor by virtue of its ability to reverse an effect that an activated ... SU6656 is a Src family kinase inhibitor developed by the biotechnology company SUGEN Inc (a subsidiary of Pharmacia) in 2000. ...
"Design of allele-specific inhibitors to probe protein kinase signaling". Current Biology. 8 (5): 257-266. doi:10.1016/S0960- ... Human protein kinases use ATP as a cofactor to phosphorylate substrate proteins. Kinases play critical roles in complex cell ... "A chemical switch for inhibitor-sensitive alleles of any protein kinase". Nature. 407 (6802): 395-401. Bibcode:2000Natur.407.. ... cell-permeable bumped inhibitors of mutant kinases. For the I338G v-Src kinase, a 4-amino-l-tert-butyl-3-(p-methylphenyl) ...
"Design of allele-specific inhibitors to probe protein kinase signaling". Current Biology. 8 (5): 257-66. doi:10.1016/s0960-9822 ... and G-protein coupled receptors such as DREADDs. DREADDs are the most common G protein-coupled receptors used in chemogenetics ... G-protein coupled receptors' usage and chemogenetics are nowadays the targets for many of the pharmaceutical companies to cure ... Having this information allows scientists understand whether viral expression of DREADD proteins, both in-vivo enhancers and ...
... which are protein kinase C inhibitors. These calphostins have cytotoxic activity due to their ability to inhibit protein kinase ... novel and specific inhibitors of protein kinase C. I. Fermentation, isolation, physico-chemical properties and biological ... novel and specific inhibitors of protein kinase C. II. Chemical structures". The Journal of Antibiotics. 42 (10): 1475-1481. ... cladosporioides can also induce respiratory inflammation due to the up-regulation of macrophage inflammatory protein (MIP)-2 ...
... C is a potent inhibitor of protein kinase C (PKC). Kobayashi, E; Ando, K; Nakano, H; Iida, T; Ohno, H; Morimoto, M; ... Iida, T; Kobayashi, E; Yoshida, M; Sano, H (1989). "Calphostins, novel and specific inhibitors of protein kinase C. II. ... The calphostins are inhibitors of protein kinase C (PKC). The most potent member of the series, calphostin C, has found use as ... Tamaoki, T (1989). "Calphostins (UCN-1028), novel and specific inhibitors of protein kinase C. I. Fermentation, isolation, ...
... is a potent inhibitor of protein kinase C (PKC). Kobayashi, E; Ando, K; Nakano, H; Iida, T; Ohno, H; Morimoto, M; ... Iida, T; Kobayashi, E; Yoshida, M; Sano, H (1989). "Calphostins, novel and specific inhibitors of protein kinase C. II. ... Tamaoki, T (1989). "Calphostins (UCN-1028), novel and specific inhibitors of protein kinase C. I. Fermentation, isolation, ...
It is a protein kinase C inhibitor. Echinacoside Taskova, Rilka Mladenova; Gotfredsen, Charlotte Held; Jensen, Søren Rosendal ( ... an Inhibitor of Protein Kinase C". Journal of Natural Products. 54 (6): 1595-600. doi:10.1021/np50078a016. PMID 1812212. ... Involvement of PARP-1 and p53 proteins". Toxicology Letters. 178 (2): 71-6. doi:10.1016/j.toxlet.2008.02.006. PMID 18395372. ... in vitro genotoxicity of verbascoside has been reported on human lymphocytes with an involvement of PARP-1 and p53 proteins, ...
... belongs to a group of medicines called protein kinase inhibitors. It works by blocking enzymes known as protein ... Roskoski R (January 2020). "The role of fibroblast growth factor receptor (FGFR) protein-tyrosine kinase inhibitors in the ... By blocking the tyrosine kinases in FGFRs, pemigatinib is expected to reduce the growth and spread of the cancer. The most ... kinases, particularly those that are part of receptors (targets) called fibroblast growth factor receptors (FGFRs). FGFRs are ...
Protein kinase inhibitors: insights into drug design from structure. Science. 2004 Mar 19;303(5665):1800-5. According to Google ... PMID: 31212132 Structure-based discovery of cyclin-dependent protein kinase inhibitors. Martin MP, Endicott JA, Noble MEM. ... to conduct research into cyclin-dependent protein kinases (CDKs). She was awarded a Royal Society University Research ... Her group studies how proteins involved in transcription and other cell cycle processes interact with each other, and whether ...
The research program started with the design of metal-based protein kinase inhibitors, the subsequent design of chiral ... "Structurally Sophisticated Octahedral Metal Complexes as Highly Selective Protein Kinase Inhibitors". Journal of the American ...
The number of protein kinases thought to exist in the human genome exceeds six hundred, making a nanomolar inhibitor such as ... cyclin-dependent kinases, G-protein coupled receptor kinases, tyrosine kinase, and cytomegalovirus pUL97 protein. Topoisomerase ... a broad protein kinase inhibitor. The next landmark discovery came with the detection of rebeccamycin (REB) in a sample of ... "Antimicrobial activities of indolocarbazole and bis-indole protein kinase C inhibitors. II. Substitution on maleimide nitrogen ...
Protein kinase inhibitor McCormick F, Fabbro D (2005). Protein Tyrosine Kinases: From Inhibitors to Useful Drugs (Cancer Drug ... Mubritinib (TAK-165) is a protein kinase inhibitor which was under development by Takeda for the treatment of cancer. It ...
... is a lyso-sphingolipid protein kinase inhibitor. It has the molecular formula C18H39NO2 and is a colorless solid. ... Potentiation of apoptosis by treatment with the protein kinase C-specific inhibitor safingol in mitomycin C-treated gastric ... Safingol is also a putative inhibitor of sphingosine kinase 1 (SphK), which catalyzes the production of sphingosine 1-phosphate ... Safingol competitively competes with phorbol dibutyrate at regulatory domains of the protein kinase C family, inhibiting the ...
"Raf kinase inhibitor protein interacts with NF-kappaB-inducing kinase and TAK1 and inhibits NF-kappaB activation". Molecular ... Cheung PC, Nebreda AR, Cohen P (Feb 2004). "TAB3, a new binding partner of the protein kinase TAK1". The Biochemical Journal. ... Ishitani T, Takaesu G, Ninomiya-Tsuji J, Shibuya H, Gaynor RB, Matsumoto K (Dec 2003). "Role of the TAB2-related protein TAB3 ... Testicular receptor 4 also known as NR2C2 (nuclear receptor subfamily 2, group C, member 2) is a protein that in humans is ...
Roskoski R (February 2020). "Properties of FDA-approved small molecule protein kinase inhibitors: A 2020 update". Pharmacol. ... Pexidartinib, sold under the brand name Turalio, is a kinase inhibitor drug for the treatment of adults with symptomatic ... Common side effects are increased lactate dehydrogenase (proteins that helps produce energy in the body), increased aspartate ... protein in red blood cells that carry oxygen), rash, dysgeusia (altered sense of taste) and decreased phosphate (electrolytes ...
... is an inhibitor of protein kinase C-beta. ", Eli Lilly and Company Announces Approvable Letter Issued by ...
It is a p38 mitogen-activated protein kinase inhibitor. A phase II trial for treatment of ovarian cancer has completed. Patnaik ... March 2016). "A First-in-Human Phase I Study of the Oral p38 MAPK Inhibitor, Ralimetinib (LY2228820 Dimesylate), in Patients ... January 2020). "A randomized, double-blind, placebo-controlled phase 1b/2 study of ralimetinib, a p38 MAPK inhibitor, plus ...
... is an ATP-competitive protein tyrosine kinase inhibitor. The main targets of dasatinib are BCR/Abl (the "Philadelphia ... It is a tyrosine-kinase inhibitor and works by blocking a number of tyrosine kinases such as Bcr-Abl and the Src kinase family ... a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays". Journal of Medicinal Chemistry. 47 (27 ... Dasatinib has been shown to induce apoptosis in senescent cells by inhibiting Src kinase, whereas quercetin inhibits the anti- ...
"Mechanism-based design of a protein kinase inhibitor". Nature Structural Biology. 8 (1): 37-41. doi:10.1038/83028. PMID ... Phosphorylation events, either phosphorylation by protein kinases or dephosphorylation by phosphatases, result in protein ... nonselective and selective kinase inhibitors, such as a class of pyridinylimidazole compounds are potent inhibitors useful in ... protein-protein interactions, protein synthesis and turnover, and enzyme activity, among others. Three general approaches for ...
ER Translocon complex.[2] Many protein complexes are involved in protein synthesis. The actual production takes place in the ... Sec61 is the protein-conducting channel and the OST adds sugar moieties to the nascent protein. ... Oligosaccharyltransferase or OST (EC is a membrane protein complex that transfers a 14-sugar oligosaccharide from ... Yeast OST is composed of eight different membrane-spanning proteins in three subcomplexes (one of them is OST4).[7][8] These ...
Tyrosine-kinase inhibitors ("-nib"). Receptor tyrosine kinase. *ErbB: HER1/EGFR (Brigatinib. *Erlotinib ... The CD20 proteins are sticking out of the cell membrane, and rituximab, the Y-shaped antibody, is binding to the CD20 proteins. ... RET inhibitors: Vandetanib (also VEGFR and EGFR). Entrectinib (ALK, ROS1, NTRK). c-MET inhibitor: Cabozantinib (also VEGFR2). ... The antibody binds to the cell surface protein CD20. CD20 is widely expressed on B cells, from early pre-B cells to later in ...
protein kinase inhibitor activity. • collagen binding. • extracellular matrix structural constituent conferring compression ... negative regulation of protein kinase activity. • cytokine-mediated signaling pathway. • negative regulation of JAK-STAT ... a newly discovered member of the leucine-rich repeat protein family". The Journal of Biological Chemistry. 276 (15): 12212-21. ... a novel member of the leucine-rich repeat protein family closely related to decorin and biglycan". The Journal of Biological ...
"Inhibitor of apoptosis proteins (IAPs) and their antagonists regulate spontaneous and tumor necrosis factor (TNF)-induced ... "The neuropeptide substance P activates p38 mitogen-activated protein kinase resulting in IL-6 expression independently from NF- ... "Metalloproteinases and transforming growth factor-alpha mediate substance P-induced mitogen-activated protein kinase activation ... Seckl MJ, Higgins T, Widmer F, Rozengurt E (Jan 1997). "[D-Arg1,D-Trp5,7,9,Leu11]substance P: a novel potent inhibitor of ...
Like lapatinib and neratinib, afatinib is a protein kinase inhibitor that also irreversibly inhibits human epidermal growth ... RET inhibitors: Vandetanib (also VEGFR and EGFR). Entrectinib (ALK, ROS1, NTRK). c-MET inhibitor: Cabozantinib (also VEGFR2). ... Afatinib is not only active against EGFR mutations targeted by first generation tyrosine-kinase inhibitors (TKIs) like ... Minkovsky N, Berezov A (December 2008). "BIBW-2992, a dual receptor tyrosine kinase inhibitor for the treatment of solid tumors ...
... quercetin is a non-specific protein kinase enzyme inhibitor.[17][20] Quercetin has also been reported to have estrogenic ( ... a pleiotropic kinase inhibitor against cancer" (PDF). (review). Cancer Treatment and Research. 159: 185-205. doi:10.1007/978-3- ... Quercetin also activates or inhibits the activities of a number of proteins.[22] For example, ... quercetin has also been found to act as an agonist of the G protein-coupled estrogen receptor (GPER).[26][27] ...
... mitogen-activated protein kinase) cascade that is itself a kinase. RSK2 phosphorylates cellular proteins (including histone H3 ... Psychiatric therapy, selective serotonin reuptake inhibitors Difficulty swallowing. Difficult time swallowing. Common. Common. ... Mutations in the RPS6KA3 gene can result in expression of an RSK2 protein (ribosomal S6 kinase 2) with reduced or absent kinase ... The protein RSK2 which is encoded by the RPS6KA3 gene is a kinase which phosphorylates some substrates like CREB and histone H3 ...
Bcr-Abl tyrosine-kinase inhibitors. *Cannabinoid receptor antagonists. *CCR5 receptor antagonists. *Neurokinin 1 receptor ... Fig 2. Schematic diagram of a GABAA receptor protein ((α1)2(β2)2(γ2)) which illustrates the five combined subunits that form ... The synaptic anchoring protein Gephyrin is indirectly linked to the GABAA receptors. ... molecules that increase the activity of the GABAA receptor protein in the vertebrate central nervous system. ...
... binding to cAMP-dependent protein kinase (PKA).[111] Moclobemide is chemically unrelated to irreversible MAOI antidepressants ... reversible inhibitor of monoamine oxidase A (RIMA),[9] a type of monoamine oxidase inhibitor (MAOI), and increases levels of ... Moclobemide (sold as Amira, Aurorix,[7] Clobemix , Depnil and Manerix[8]) is a reversible inhibitor of monoamine oxidase A ( ... Cesura AM, Pletscher A (1992). The new generation of monoamine oxidase inhibitors. Prog Drug Res. 38. pp. 171-297. doi:10.1007/ ...
positive regulation of protein kinase activity. • T cell activation involved in immune response. • cellular protein metabolic ... the full length protein accumulates in an inactive form.[10] Based on evidence that a gamma-secretase inhibitor binds to the ... protein processing. • protein maturation. • myeloid dendritic cell differentiation. • autophagy. • protein glycosylation. • ... negative regulation of protein kinase activity. • cell fate specification. • skeletal system morphogenesis. • regulation of ...
is modified to include binding of the inhibitor to the free enzyme:. EI. +. S. ⇌. k. 3. k. −. 3. E. +. S. +. I. ⇌. k. −. 1. k. ... The active site is a region on an enzyme which a particular protein or substrate can bind to. The active site will only allow ... is the inhibitor concentration.. V. max. {\displaystyle V_{\max }}. remains the same because the presence of the inhibitor can ... To compute the concentration of competitive inhibitor [. I. ]. {\displaystyle {\ce {[I]}}}. that yields a fraction f. V. 0. {\ ...
"Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired ... Genetic disorder, protein biosynthesis: Transcription factor/coregulator deficiencies. (1) Basic domains. 1.2. *Feingold ... C1-inhibitor (Angioedema/Hereditary angioedema). *Complement 2 deficiency/Complement 4 deficiency. *MBL deficiency ...
TANGO6: encoding protein Transport and Golgi organization protein 6 homolog. *TAO2: encoding Serine/threonine-protein kinase ... CIAPIN1: Anamorsin (originally, Cytokine induced apoptosis inhibitor 1). *CKLF: Chemokine-like factor ... UNKL: encoding protein RING finger protein unkempt-like. *VAT1L: encoding protein Vesicle amine transport protein 1 homolog (T ... LINC00273 encoding protein Long intergenic non-protein coding RNA 273. *LOC124220: encoding protein Zymogen granule protein 16 ...
This bacterial protein complex is a machine for folding other proteins, which get trapped within the shell. Fatty acid synthase ... Arias-Palomo E, Recuero-Checa MA, Bustelo XR, Llorca O (December 2007). "3D structure of Syk kinase determined by single- ... Å resolution cryo-EM structure of β-galactosidase in complex with a cell-permeant inhibitor". Science. 348 (6239): 1147-1151. ... Proteins in vitreous ice usually adopt a random distribution of orientations (or viewing angles), allowing a fairly isotropic ...
Dalam bidang kimia telah digunakan untuk menyatakan selektivitas protein inhibitor kinase terhadap panel kinase.[20] In ... Graczyk, Piotr (2007). "Gini Coefficient: A New Way To Express Selectivity of Kinase Inhibitors against a Family of Kinases". ...
Type 3: Kinase-linked and related receptors (see "Receptor tyrosine kinase" and "Enzyme-linked receptor") - They are composed ... Ligands connect to specific receptor proteins based on the shape of the active site of the protein. ... The proton pump inhibitor omeprazole is an example of an irreversible antagonist. The effects of irreversible antagonism can ... and can be a protein or peptide (short protein), or another small molecule such as a neurotransmitter, hormone, pharmaceutical ...
"Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Archived from the original on 4 March 2016. Retrieved 23 March 2015.. ... 2003). "Cloning and characterization of a novel cardiac-specific kinase that interacts specifically with cardiac troponin I.". ... The encoded protein can also bind RNA and decreases the stability of some mRNAs. The genes of the alpha and beta subunits of ... The HADHB protein catalyzes the final step of beta-oxidation, in which 3-ketoacyl CoA is cleaved by the thiol group of another ...
Wnt-protein binding. • protein binding. • protein kinase binding. • ubiquitin protein ligase binding. • transmembrane signaling ... positive regulation of protein targeting to mitochondrion. • positive regulation of JUN kinase activity. • apoptotic process ... gene family encode 7-transmembrane domain proteins that are receptors for Wnt signaling proteins. The FZD5 protein is believed ... G-protein coupled receptor activity. Cellular component. • clathrin-coated endocytic vesicle membrane. • Golgi apparatus. • ...
"Neuronal Cdc2-like protein kinase (Cdk5/p25) is associated with protein phosphatase 1 and phosphorylates inhibitor-2". J. Biol ... positive regulation of protein kinase activity. • regulation of cyclin-dependent protein serine/threonine kinase activity. • ... 2004). "Regulation of type 1 protein phosphatase/inhibitor-2 complex by glycogen synthase kinase-3beta in intact cells". J. ... cyclin-dependent protein kinase 5 activator activity. • lipid binding. Cellular component. • cytoplasm. • cyclin-dependent ...
cAMP binds to and releases an active form of protein kinase A (PKA). Next, PKA phosphorylates phosphorylase kinase, which, in ... This site was not sensitive to the same inhibitors as those at the AMP allosteric site,[12] and most success has been had ... I. Isolation and characterization of the protein-glycogen complex". Journal of Biological Chemistry. 245 (24): 6642-6648. PMID ... First, the catalytic sites are relatively buried, 15Å from the surface of the protein and from the subunit interface.[6] This ...
protein kinase inhibitor activity. • histone binding. • Tat protein binding. • NF-kappaB binding. • ligação a proteínas ... protein oligomerization. • negative regulation of protein kinase activity by regulation of protein phosphorylation. • ... protein heterodimerization activity. • nucleic acid binding. • protein kinase binding. • core promoter binding. • RNA ... protein stabilization. • protein homooligomerization. • regulation of cell cycle. • positive regulation of protein localization ...
Murphy CI, Lennick M, Lehar SM, Beltz GA, Young E (October 1990). "Temporal expression of HIV-1 envelope proteins in ... Fenouillet E, Gluckman JC (August 1991). "Effect of a glucosidase inhibitor on the bioactivity and immunoreactivity of human ... Three transcript variants encoding the same protein have been found for this gene.[6] ... Phosphorylase kinase. *Protein phosphatase. This article on a gene on human chromosome 17 is a stub. You can help Wikipedia by ...
positive regulation of non-membrane spanning protein tyrosine kinase activity. • transmembrane receptor protein tyrosine kinase ... Blockading BDNF signaling with a tyrosine kinase inhibitor or a PKC inhibitor in wild type mice produced significant reductions ... Tropomyosin receptor kinase B § Agonists. References[edit]. *^ a b c GRCh38: Ensembl release 89: ENSG00000176697 - Ensembl, May ... an effect that was abolished in either the presence of a specific NR2B antagonist or a trk receptor tyrosine kinase inhibitor.[ ...
HER2 kinase inhibitors, such as lapatinib, have also demonstrated clinical efficacy in HER2 overexpressing breast cancers by ... the Wnt signaling pathway leads to stabilization of β-catenin through inactivation of a protein complex containing the tumor ... EGFR-specific tyrosine kinase inhibitors such as gefitinib have shown limited therapeutic success. This resistance is proposed ... "Neuregulin-1-Mediated Autocrine Signaling Underlies Sensitivity to HER2 Kinase Inhibitors in a Subset of Human Cancers". Cancer ...
The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. „Cell". 75 (4), s. 805-816, 1993. ... Li Y, Jenkins CW, Nichols MA, Xiong Y. Cell cycle expression and p53 regulation of the cyclin-dependent kinase inhibitor p21. „ ... a b Entrez Gene: CDKN1A cyclin-dependent kinase inhibitor 1A (p21, Cip1). ... Phosphorylation of the cell cycle inhibitor p21Cip1/WAF1 by Pim-1 kinase. „Biochim. Biophys. Acta". 1593 (1), s. 45-55, 2002. ...
Inhibitor resorpcije (Ipriflavon) • Aluminijum hlorohidrat • Koštani agens dualnog dejstva (Stroncijum ranelat) • RANKL ... a new oligomerization mode for serine/threonine kinase receptors". Mol. Biol. Cell 11 (3): 1023-35. PMC 14828. PMID 10712517. ... Koštani morfogenetički protein 2 ili BMP-2 pripada TGF-β superfamiliji proteina.[1] ... Chen D, Zhao M, Mundy GR (December 2004). "Bone morphogenetic proteins". Growth Factors 22 (4): 233-41. PMID 15621726. doi: ...
FQ/nociceptin-mediated desensitization of opioid receptor-like 1 receptor and mu opioid receptors involves protein kinase C: a ... Moždano specifični angiogenezni inhibitor (1, 2, 3) • Kadherin (1, 2, 3) • Kalcitonin • CALCRL • CD97 • Kortikotropin- ... Nociceptinski receptor (NOP, orfaninski FQ receptor, kapa tip 3 opioidni receptor) je protein koji je kod čoveka kodiran OPRL1 ... signalni put G-protein spregnutog receptora. • G-proteinska signalizacija, inhibicioni put adenilat ciklaze. • elevacija ...
... or to result from the differential activity of the pro-apoptotic kinase JNK.[89] The ability of proteasome inhibitors to induce ... The protein degradation processEdit. Ribbon diagram of ubiquitin, the highly conserved protein that serves as a molecular tag ... Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks ... Proteins are tagged for degradation with a small protein called ubiquitin. The tagging reaction is catalyzed by enzymes called ...
Hunter T (January 1995). "Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling". 》Cell》 ... "Allosteric small-molecule kinase inhibitors" (PDF). 》Pharmacology & Therapeutics》 (영어) 156: 59-68. doi:10.1016/j.pharmthera. ... Protein structure and function》. London: New Science. 27쪽. ISBN 978-1405119221. .. ... Anfinsen CB (July 1973). "Principles that govern the folding of protein chains". 》Science》 181 (4096): 223-30. Bibcode:1973Sci ...
"Hyperphosphorylation of a novel 80 kDa protein-tyrosine kinase similar to Ltk in a human Ki-1 lymphoma cell line, AMS3". ... CD30, also known as TNFRSF8, is a cell membrane protein of the tumor necrosis factor receptor family and tumor marker. ... Proteins: clusters of differentiation (see also list of human clusters of differentiation) ... "A variant CD30 protein lacking extracellular and transmembrane domains is induced in HL-60 by tetradecanoylphorbol acetate and ...
... and methods of using them to treat tyrosine kinase-dependent diseases and conditions in mammals: wherein n is an integer, ... regulate and/or modulate tyrosine kinase signal transduction, compositions which contain these compounds, ... Protein tyrosine kinase inhibitors. US20090298855 *. Jul 28, 2009. Dec 3, 2009. Critical Outcome Technologies Inc.. Protein ... prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors ...
... Lew Jacobson LJAC at VMS.CIS.PITT.EDU Wed May 3 12:01:09 EST 1995 *Next ... Does anyone have any experience using PKC inhibitors (e.g., staurosporine, calphostin C, HA-1077) or protein phosphatase ... What about selectivity of the PKC inhibitors? Any information or references will be much appreciated. _/ _/_/_/_/ _/_/_/_/_/ ... inhibitors (e.g., okadaic acid, calyculin A) on C. elegans in vivo? Which ones work (if any) and by what criteria? Any ...
Pharmacological Actions : Antiproliferative , Apoptotic, Cell cycle arrest, Protein Kinase Inhibitors, Tumor Suppressor Protein ... Pharmacological Actions : Antiproliferative , Cell cycle arrest, Chemopreventive, Enzyme Inhibitors, Protein Kinase Inhibitors ... Protein Kinase Inhibitors, Tumor Necrosis Factor (TNF) Alpha Inhibitor. Additional Keywords : Adlay, Anti-Allergic Agents, ... 17 Abstracts with Protein Kinase Inhibitors Research. Filter by Study Type. Animal Study. ...
... threonine-specific protein kinases have been examined against a large panel of protein kinases. The compounds KT 5720, ... but still inhibited two or more protein kinases with similar potency. LY 294002 was found to inhibit casein kinase-2 with ... Rottlerin and quercetin were found to inhibit many protein kinases, sometimes much more potently than their presumed targets, ... Ro 318220 and related bisindoylmaleimides, as well as H89, HA1077 and Y 27632, were more selective inhibitors, ...
Mitogen-activated protein kinase kinase kinase 2. target. DB06616. Bosutinib. Calcium/calmodulin-dependent protein kinase type ... cAMP-dependent protein kinase inhibitor alpha. target. DB08162. Fasudil. cAMP-dependent protein kinase catalytic subunit alpha ... Serine/threonine-protein kinase B-raf. target. DB08912. Dabrafenib. RAF proto-oncogene serine/threonine-protein kinase. target ... Receptor-type tyrosine-protein kinase FLT3. target. DB00398. Sorafenib. RAF proto-oncogene serine/threonine-protein kinase. ...
Hints: Click on a [map] link to show a map of that region. Click on a [studies] link to search within your current results for studies in that region. Use the back button to return to this list and try another region. Studies with no locations are not included in the counts or on the map. Studies with multiple locations are included in each region containing locations ...
A synthetic inhibitor of the mitogen-activated protein kinase cascade. D T Dudley, L Pang, S J Decker, A J Bridges, A R Saltiel ... A synthetic inhibitor of the mitogen-activated protein kinase cascade. D T Dudley, L Pang, S J Decker, A J Bridges, A R Saltiel ... A synthetic inhibitor of the mitogen-activated protein kinase cascade. D T Dudley, L Pang, S J Decker, A J Bridges, and A R ... A synthetic inhibitor of the mitogen-activated protein kinase cascade Message Subject (Your Name) has sent you a message from ...
... Halyna M. Kuznietsova, Maryna S. Yena, Iryna P. Kotlyar ... "Anti-Inflammatory Effects of Protein Kinase Inhibitor Pyrrol Derivate," The Scientific World Journal, vol. 2016, Article ID ...
... Halyna M. Kuznietsova, Maryna S. Yena, Iryna P. Kotlyar ... In our previous studies we showed antitumor and anti-inflammatory activities of protein kinases inhibitor pyrrol derivate 1-(4- ... Increase of malonic dialdehyde (MDA) by 89% and protein carbonyl groups (PCG) by 60% and decrease of superoxide dismutase (SOD ...
Protein kinase CK-1 inhibitors as new potential drugs for amyotrophic lateral sclerosis.. Salado IG1, Redondo M, Bello ML, ... Protein Kinase CK-1 Inhibitors As New Potential Drugs for Amyotrophic Lateral Sclerosis ... Protein Kinase CK-1 Inhibitors As New Potential Drugs for Amyotrophic Lateral Sclerosis ... Protein Kinase CK-1 Inhibitors As New Potential Drugs for Amyotrophic Lateral Sclerosis ...
Kinases and kinase inhibitors Chemical Biology for Target Identification and Validation ... and identify cellular targets from cell lysates and tissues is of great utility for kinase inhibitor drug discovery. We ... Rapid profiling of protein kinase inhibitors by quantitative proteomics† Martin Golkowski,‡*a Jennifer L. Brigham,‡*b B. Gayani ... Rapid profiling of protein kinase inhibitors by quantitative proteomics M. Golkowski, J. L. Brigham, B. G. K. Perera, G. S. ...
To test the hypothesis that PKC inhibition would decrease persistence of potentiation we applied PKC inhibitors (mellitin, ... Recent findings suggest that protein kinase C (PKC) regulates the persistence of long-term potentiation (LTP). ... Protein kinase C inhibitors eliminate hippocampal long-term potentiation Brain Res. 1987 Dec 8;436(1):177-83. doi: 10.1016/0006 ... Recent findings suggest that protein kinase C (PKC) regulates the persistence of long-term potentiation (LTP). To test the ...
Various inhibitors of PKG were developed directed against diverse functional regions of the kinase. These inhibitors of PKG ... The review article will summarize these different inhibitors regarding their specificity and their present applications in ... which expresses the membrane associated PKG-II protein. The enzyme kinetics, the localization and the substrates of these PKG ... cGMP-dependent protein kinases (PKG) exhibit diverse physiological functions in the mammalian system e.g., in vascular and ...
... protein kinases; protein phosphorylation; signal proteins; threonine residues ... Protein kinases (PKs) are key components of protein phosphorylation based signaling networks in eukaryotic cells. They have ... Our aim is that researchers working in the design of PK inhibitors be aware of the benefits of this powerful tool in the design ... Keywords: 4D-QSAR; Molecular dynamics; PK inhibitors; X-ray crystallographic data; docking; free energy calculations; ...
... treat tyrosine kinase-dependent diseases and conditions in mammals: ##STR00001## wherein n is an integer, preferably n is 1; ... regulate and/or modulate tyrosine kinase signal transduction, compositions which contain these compounds, and methods of using ... prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors ... a tyrosine kinase inhibitor, an inhibitor of epidermal-derived growth factor, an inhibitor of fibroblast-derived growth factor ...
Suppliers of: Protein Kinase C Inhibitor. Found 8 Companies HOW TO USE BSN RAPID REQUEST. To send a request for quote/ ...
cAMP-dependent protein kinase inhibitor alpha. I, J, K. 20. N/A. Mutation(s): 0 ... Human cyclic AMP-dependent protein kinase PKA inhibitor complex. *DOI: 10.2210/pdb3MVJ/pdb ... cAMP-dependent protein kinase catalytic subunit alpha. A, B, E. 371. Homo sapiens. Mutation(s): 0 Gene Names: PKA, PKACA, ... Design of selective, ATP-competitive inhibitors of Akt.. Freeman-Cook, K.D., Autry, C., Borzillo, G., Gordon, D., Barbacci- ...
... Development of Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitors with Potent Anti-Toxoplasma Activity ... Development of Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitors with Potent Anti-Toxoplasma Activity ... Development of Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitors with Potent Anti-Toxoplasma Activity ...
... recombinant proteins & enzymes, and other innovative research tools for studying Apoptosis, Metabolism, Cell Proliferation, ... 700 Protein Kinase Inhibitors as part of its product portfolio. BioVision also manufactures and markets sets of protein kinase ... 500 protein kinase genes constituting a whopping 2% of the total number of human genes. Protein Kinases thus form a very ... Tyrosine Kinases (the Insulin Receptor), Histidine Kinases (common in Prokaryotes).. Protein kinases are one of the most ...
The PDB archive contains information about experimentally-determined structures of proteins, nucleic acids, and complex ... Protein Feature View of PDB entries mapped to a UniProtKB sequence * Number of PDB entries for Q5U0H2: no matching PDB entries ... This protein in other organisms (by gene name): Q5U0H2 - Homo sapiens 0 * Q16307 - Homo sapiens no matching PDB entries ... Potent inhibitor of cyclin E- and cyclin A-CDK2 complexes. Forms a complex with cyclin type D-CDK4 complexes and is involved in ...
O hydrogen bonds in protein-ligand complexes. In this work, we present evidence for such nonstandard hydrogen bonds from a ... Kinase inhibitors and the case for CH...O hydrogen bonds in protein-ligand binding Proteins. 2002 Dec 1;49(4):567-76. doi: ... with nicotinamide and heterocycles preferred in kinase inhibitors showing particularly favorable interactions. These results ... In this work, we present evidence for such nonstandard hydrogen bonds from a survey of aromatic ligands in 184 kinase crystal ...
Suppliers of: Inhibitors of Protein Kinases and Phosphatases. Found 16 Companies HOW TO USE BSN RAPID REQUEST. To send a ...
Protein Kinase Inhibitors in Research and Medicine has 1 available editions to buy at Alibris ... Protein Kinase Inhibitors in Research and Medicine by Kevan M Shokat starting at $153.99. ... Protein Kinase Inhibitors in Research and Medicine. by Kevan M Shokat Write The First Customer Review ... This volume covers protein kinase inhibitors in research and medicine, and includes chapters on such topics as fragment-based ...
... recombinant proteins & enzymes, and other innovative research tools for studying Apoptosis, Metabolism, Cell Proliferation, ... Protein kinase C (PKC) are enzymes that add phosphate-groups to Serine/Threonine residues on a large variety of target proteins ... specific inhibitors are sought to understand the function of each isoform and target proteins involved in different diseases. ... PKCs are curiously versatile enzymes in the sense that they can not only function as kinases but also as phosphatases and ...
... cell growth is driven by a group of enzymes known as receptor tyrosine kinases. In the current issue of the Journal of Clinical ... New class of proteins allows breast cancer cells to evade tyrosine kinase inhibitors. JCI Journals ... New class of proteins allows breast cancer cells to evade tyrosine kinase inhibitors ... known as tyrosine kinase inhibitors (TKIs) have not been effective in treating breast cancer. Researchers believe that the ...
This study provides new insights into TKI resistance and drug repositioning of DPP4 inhibitor as a promising strategy for ... has been recently identified as a cancer stemness-related protein. A question arises whether DPP4 contributes to TKI efficacy ... higher TKI efficacy is observed in those bearing DPP4high tumors treated with DPP4 inhibitors. ... Tyrosine kinase inhibitors (TKIs) are used as targeted drugs for advanced renal cell carcinoma (RCC), although most cases ...
Shop a large selection of Protease Inhibitors and Phosphatase Inhibitors products and learn more about MilliporeSigmaCalbiochem ... The p38 MAP Kinase Inhibitor X, BIRB 796, also referenced under CAS 285983-48-4, controls the biological activity of p38 MAP ... This small molecule/inhibitor is primarily used for Phosphorylation & Dephosphorylation applications.. Manufacturer: ... p38 MAP Kinase Inhibitor X, BIRB 796. 10mg. ... MilliporeSigma™ Calbiochem™ p38 MAP Kinase Inhibitor X, BIRB ...
Potent inhibitor of cyclin E- and cyclin A-CDK2 complexes. Forms a complex with cyclin type D-CDK4 complexes and is involved in ... Acts either as an inhibitor or an activator of cyclin type D-CDK4 complexes depending on its phosphorylation state and/or ... Inhibits the kinase activity of CDK2 bound to cyclin A, but has little inhibitory activity on CDK2 bound to SPDYA. Involved in ... cyclin-dependent protein serine/threonine kinase inhibitor activity Source: UniProtKB. *protein-containing complex binding ...
Protein Kinase C (PKC) Inhibitor-Diabetic Retinopathy Phase 3 Study. This study has been completed. ...
... this protein interacts with the catalytic subunit of the enzyme after the cAMP-induced dissociation of its regulatory chains. ... Extremely potent competitive inhibitor of cAMP-dependent protein kinase activity, ... Extremely potent competitive inhibitor of cAMP-dependent protein kinase activity, this protein interacts with the catalytic ... "The alpha- and beta-isoforms of the inhibitor protein of the 3,5-cyclic adenosine monophosphate-dependent protein kinase: ...
  • Treatment of cells with a variety of growth factors triggers a phosphorylation cascade that leads to activation of mitogen-activated protein kinases (MAPKs, also called extracellular signal-regulated kinases, or ERKs). (
  • Pathological TDP-43 phosphorylation appears to drive the onset and progression of ALS and may result from upregulation of the protein kinase CK-1 in affected neurons, resulting in postranslational TDP-43 modification. (
  • We observed surprisingly high sequence coverage on some proteins, enabling further analyses of phosphorylation sites for several target kinases without additional sample processing. (
  • Protein kinases (PKs) are key components of protein phosphorylation based signaling networks in eukaryotic cells. (
  • citation needed] Phosphorylation regulates many biological processes, and protein kinase inhibitors can be used to treat diseases due to hyperactive protein kinases (including mutant or overexpressed kinases in cancer) or to modulate cell functions to overcome other disease drivers. (
  • Phosphorylation is the most widely prevalent bio-chemical modification (up to 30% of all human proteins can be regulated via phosphorylation) that can change the activity of a protein or regulate an enzyme by turning it on or off. (
  • Kinases are turned on or off by phosphorylation (sometimes by the kinase itself - cis-phosphorylation also known as autophosphorylation), by binding of activator or inhibitor proteins, or small molecules, or by controlling their location in the cell relative to their substrates. (
  • Acts either as an inhibitor or an activator of cyclin type D- CDK4 complexes depending on its phosphorylation state and/or stoichometry. (
  • This small molecule/inhibitor is primarily used for Phosphorylation & Dephosphorylation applications. (
  • MAPK forms the backbone of four primary signal transduction cascades leading to the phosphorylation and activation of extracellular signal-regulated kinases 1 and 2 (ERK1--2), JNK, p38 and ERK5. (
  • A more potent synthetic derivative of quercitin, LY294002, also inhibits enzymatic phosphorylation of lipids and proteins ( 11 ). (
  • The protein kinase prevents the phosphorylation of the specific amino acid , such as tyrosine. (
  • OVA-induced Src phosphorylation was abrogated by Src inhibitors, but not affected by inhibitors of EGFR and Rho-kinase. (
  • Inhibitors of Src and EGFR, but not Rho-kinase, also blocked OVA-induced EGFR phosphorylation. (
  • Furthermore, a metalloproteinase inhibitor TAPI-0 and an inhibitor of heparin-binding EGF not only abrogated the OVA-induced aortic contraction, but also OVA-induced EGFR and MYPT1 phosphorylation, suggesting the involvement of EGFR transactivation. (
  • Effects of treatment were measured in terms of cytotoxicity, cellular morphology, viability, apoptosis, phosphorylation of protein kinase B (Akt), and anabolic/catabolic gene expression analyses related to cartilage tissue. (
  • Inhibition of Erk1/2 phosphorylation with a MEK specific inhibitor enhanced the sensitivity of GNAQ wild type cells to enzastaurin, accompanied by p27\(^{Kip1}\) accumulation and/or inhibition of enzastaurin-induced survivin and Bcl-2 upregulation. (
  • IKKα, IKKβ, and IKKγ are the core components of a 700- to 900-kDa multimolecular kinase complex, which is responsible for stimulus-induced phosphorylation of IκBs ( 16 , 17 , 18 , 19 , 20 , 21 , 22 ). (
  • Phosphorylation of vascular and renal extracellular-signal-regulated protein kinase 1/2 (ERK1/2), p38MAP kinase and c-Jun N-terminal kinase (JNK) were assessed using phospho-specific antibodies. (
  • Quinidine and imipramine reduced the phosphorylation of renal ERK1/2, but did not modify renal p38MAP kinase or JNK. (
  • Our data demonstrate that Ang II induces severe hypertension in Sprague-Dawley rats and this is associated with increased phosphorylation of vascular and renal MAP kinases. (
  • We show here that cingulin is phosphorylated in vivo on serine, and its specific phosphorylation is not significantly changed by treatment of confluent MDCK monolayers with PMA, with the protein kinase inhibitor H-7, or with the calcium chelator EGTA. (
  • During junction assembly by calcium switch, H-7 did not change the specific phosphorylation of the immunoprecipitated cingulin, however, it prevented the increase in the amount of cingulin in the immunoprecipitates, suggesting that H-7 may block tight junction assembly by interfering with cellular processes that lead to the accumulation and stabilization of TJ proteins at sites of cell-cell contact. (
  • Evidence is accumulating that the activity of spinach (Spinacia oleracea L.) leaf NADH:nitrate reductase (NR) is modulated both in vitro and in vivo by protein phosphorylation. (
  • We identified NR-protein kinase (NR-PK) as a calcium-dependent and metabolite-regulated protein kinase and have provided additional evidence that phosphorylation of NR is necessary but not sufficient to inactivate the enzyme. (
  • The myristoylated peptide, myr-psi PKC, inhibits phosphorylation of the myristoylated alanine-rich C kinase substrate protein, as induced by 12-O-tetradecanoyl-phorbol-13-acetate, and the activation of phospholipase D by bradykinin, which strictly depends on PKC. (
  • Protein kinases are important regulators of cell functions that utilize a process known as phosphorylation. (
  • In phosphorylation, phosphate groups are added to specific binding sites on other proteins resulting in a physical conformational change that can turn on or off the activity of the molecule. (
  • In addition, we observed that cdk5 has a stronger preference for a proline and basic residues on the carboxyl-terminal side of the phosphorylation site when compared to the preference exhibited by cdc2 kinase. (
  • Publications] Ando, S.: 'Keratin 8 phosphorylation in vitro by cAMP-dependent protein kinase occurs within the amino-and carboxyl-terminal end domains. (
  • Publications] Ando, S: 'Keratin 8 phosphorylation in vitro by cAMP-dependent protein kinase occurs within the amino-and carboxyl-terminal end domains' Biochem.Biophys.Res.Commun. (
  • To test the hypothesis that PKC inhibition would decrease persistence of potentiation we applied PKC inhibitors (mellitin, polymyxin B, H-7) by micropressure ejection to the intact hippocampus either before or after LTP induction. (
  • The presence of a unique glycine gatekeeper residue in TgCDPK1 permits selective inhibition of the parasite enzyme over human kinases. (
  • Fig. 2: DPP4 inhibition enhances tumor-suppressive efficacy of tyrosine kinase inhibitor sunitinib in patient-derived renal cell carcinoma (RCC) spheroid cultures. (
  • Inhibition of DNA-dependent protein kinase catalytic subunit by small molecule inhibitor NU7026 sensitizes human leukemic K562 cells to benzene metabolite-induced apoptosis. (
  • These moderately potent nonselective kinase inhibitors have cellular activity, but it has been difficult to unambiguously distinguish the effects of protein kinase from lipid kinase inhibition ( 12 -17 ). (
  • The present study was conducted to compare the effect of PKC inhibition by a PKC-beta-selective inhibitor, LY333531 (LY), on diabetic nerve dysfunction with that of an aldose reductase inhibitor, NZ-314 (NZ). (
  • PKC inhibitors such as enzastaurin have activity against UM cells carrying GNAQ mutations through inhibition of the PKC/Erk1/2 pathway and induction of G1 arrest and apoptosis. (
  • 8. The present study showed that inhibition of protein kinase C during long-term hypothermic storage significantly increased high-energy phosphate concentrations and also improved contractile function during reperfusion. (
  • Inhibition of insulin-dependent lipogenesis and anti-lipolysis by protein tyrosine kinase inhibitors. (
  • Radiosensitization of human tumor cells by the phosphatidylinositol3-kinase inhibitors wortmannin and LY294002 correlates with inhibition of DNA-dependent protein kinase and prolonged G2-M delay. (
  • This suggests the accumulation of significant unrepaired DNA damage following inhibition of PI 3-kinase family members. (
  • Both 1 and 2 showed potent and selective protein kinase inhibition in vitro. (
  • Using partially purified inhibitor protein and NR-PK, we characterized NR inactivation (increased sensitivity to Mg2+ inhibition) in a reconstituted in vitro system. (
  • In incubations with human liver microsomes, quinidine, an inhibitor of CYP2D6, demonstrated little inhibition of metabolite formation while ketoconazole, an inhibitor of CYP3A, demonstrated almost complete inhibition. (
  • Bacterial killing by these HPK inhibitors may therefore be due to multiple mechanisms, independent of HPK inhibition. (
  • The implication of the auroras in tumourigenesis and the fact that that they are kinases, amenable to small molecule inhibition, makes them attractive targets for anticancer drug development. (
  • The specificities of 28 commercially available compounds reported to be relatively selective inhibitors of particular serine� threonine-specific protein kinases have been examined against a large panel of protein kinases. (
  • The phosphate groups are usually added to serine, threonine, or tyrosine amino acids on the protein: most kinases act on both serine and threonine, the tyrosine kinases act on tyrosine, and a number (dual-specificity kinases) act on all three. (
  • Protein kinases are often categorized based on the amino acid residues they phosphorylate: Serine/Threonine kinases (e.g. (
  • Protein kinase C (PKC) are enzymes that add phosphate-groups to Serine/Threonine residues on a large variety of target proteins to regulate their activity in different signal transduction cascades affecting a multitude of cellular processes. (
  • Among these different pathways, Ras interaction with and activation of Raf serine/threonine kinases (Raf-1, A-Raf, and B-Raf), phosphatidylinositol 3-kinases, and Ral guanine nucleotide exchange factors has been shown to be critical for tumor promotion. (
  • Casein kinase 2 (CK2), a member of the serine/threonine kinase family, has antiapoptotic properties and plays a vital role in glial tumour cell survival. (
  • cdkn2d has several biochemical functions, for example, cyclin-dependent protein serine/threonine kinase inhibitor activity, protein binding, protein kinase binding. (
  • We have identified a synthetic inhibitor of the MAPK pathway. (
  • PD 098059 [2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one] selectively inhibited the MAPK-activating enzyme, MAPK/ERK kinase (MEK), without significant inhibitory activity of MAPK itself. (
  • MAPK kinases 1 and 2, commonly known at MEK1--2, are referred to as MEK. (
  • Several inhibitors of MEK1--2 (MAPK kinases 1 and 2) are nearing, or are currently in, clinical trials for oncology. (
  • To further elucidate their anti-inflammatory mechanisms, the impact of MS-275 and SAHA on the p38 mitogen-activated protein kinase (MAPK) signaling pathway and chemotaxis was assessed in human rheumatoid arthritic synovial fibroblastic E11 cells. (
  • In summary, suppression of the p38 MAPK signaling pathway and chemotaxis appear to be important anti-rheumatic mechanisms of action of these HDAC inhibitors. (
  • This analysis showed that MCP compounds inhibited Ras-induced activation of the Raf and ERK mitogen-activated protein kinase (MAPK) signaling cascade, Ras-induced cell migration, morphologic changes and anchorage-independent growth, and Ras-regulated expression of matrix metalloproteases and cyclin D1 ( 7 ). (
  • The purpose of this study was to investigate the usefulness of a p38 MAPK inhibitor for promoting proliferation of human corneal endothelial cells (HCECs). (
  • Activation of substrates of p38 MAPK and cell cycle regulatory proteins were evaluated by western blotting. (
  • Activation of p38 MAPK signaling due to culture stress might suppress the proliferation of HCECs, whereas a p38 MAPK inhibitor can counteract this activation and enable efficient in vitro HCEC expansion. (
  • In the present study we investigated the effects of the inhibitors of mitogen-activated protein kinase (MAPK) pathways Erk1/2, p38, and JNK on COX-2 expression and prostaglandin E2 (PGE2) production in human chondrocytes. (
  • The stress-activated protein kinase (SAPK) and mitogen-activated protein kinase (MAPK) subfamilies are crucial to environmental stress responses and responses to growth factors that cause transcriptional activation of genes required for cell proliferation, differentiation and programmed cell death. (
  • In addition, sitespecific mutagenesis of MAPKs has helped identify the MAPK structures required for binding recognition and selectivity of these inhibitors. (
  • The efficacy of SAPK/MAPK inhibitors in animal models of inflammation, arthritis, heart failure, cancer and neurological degeneration has provided the impetus for using them in human studies of inflammation and in clinical trials. (
  • Mitogen-activated protein kinase kinase (MEK or MAPK/ERK kinase) is a critical enzyme in the RAS/RAF/MEK/ERK pathway that regulates key cellular activities including proliferation, survival, and cell cycle regulation. (
  • Curcumin has anti-breast cancer activity related to the activities of protein kinases on cell signal pathway. (
  • MEK1/2 proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. (
  • To improve the effectiveness of these treatments, we have identified a new class of protein kinase inhibitor that targets a major DNA repair pathway. (
  • A major pathway for the repair of DSB is nonhomologous end joining, which requires DNA-dependent protein kinase (DNA-PK) activity. (
  • Many other proteins and enzymes modulate this pathway, including PKI, a highly specific inhibitor of PKA. (
  • Mitogen-activated Protein/Extracellular Signal-regulated Kinase Kinase (MEK) Inhibitors Restore Anoikis Sensitivity in Human Breast Cancer Cell Lines with a Constitutively Activated Extracellular- regulated Kinase (ERK) Pathway 1 This work was supported by a Grant-in-Aid for Cancer Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. (
  • Thus, susceptibility of the p70 S6K pathway to MEK inhibitors appeared to be an important determinant of anoikis sensitivity. (
  • In both a defined K-Ras-transformed fibroblast model and in human tumor cell lines with mutationally activated Ras, MCP110 selectively synergizes with other agents targeting the mitogen-activated protein kinase pathway, and with multiple agents (paclitaxel, docetaxel, and vincristine) targeting the microtubule network. (
  • In one approach, a single signaling pathway is "vertically" targeted, with drugs inhibiting multiple steps in a signaling cascade: For example, pretreatment of A549 lung carcinoma cells with the phosphatidylinositol 3-kinase inhibitor PX-866, which strongly potentiates the action of the epidermal growth factor receptor inhibitor Iressa ( 9 ). (
  • We demonstrate that this assay can be used to identify specific and general inhibitors as well as activators of the signal transduction pathway mediated by PKC isozymes. (
  • One example is activation of the c-Jun N-terminal kinase (JNK) cascade and another engagement of the NF-κB pathway ( 7 , 8 ). (
  • ii) the oncogenic switch to another pathway that rescues cancer cells from kinase blockade. (
  • ii) thyroid cancer cells escape treatment with vemurafenib by switching to another signaling pathway and that inhibitors of the IGF1R/PI3K/AKT signaling cascade may be exploited to overcome resistance of thyroid cancer cells lines to BRAF PKI. (
  • PD98059 (an inhibitor of Erk1/2 pathway) suppressed IL-1-induced COX-2 expression and PGE2 production in a dose-dependent manner, and seemed to have an inhibitory effect on COX-2 activity. (
  • SB203580 (an inhibitor of p38 pathway) but not its negative control compound SB202474 inhibited COX-2 protein and mRNA expression and subsequent PGE2 synthesis at micromolar drug concentrations. (
  • This pathway is composed of a protein kinase cascade in which RAF, MEK, and ERK are in a sequential order. (
  • The inhibitors in this library will be useful for target identification in drug discovery, biochemical pathway analysis, screening new protein kinases, and other pharmaceutical-related applications. (
  • Also, other proteins which involved in the same pathway with cdkn2d were listed below. (
  • Protein Kinase C Inhibitor and Irradiation-induced Apoptosis: Relevance of the Cytochrome c-mediated Caspase-9 Death Pathway -- Rocha et al. (
  • We have previously shown that the protein kinase inhibitor β (PKIβ) form of the cAMP-dependent protein kinase inhibitor exists in multiple isoforms, some of which are specific inhibitors of the cAMP-dependent protein kinase, whereas others also inhibit the cGMP-dependent enzyme [Kumar, Van Patten and Walsh (1997), J. Biol. (
  • PKIB, also known as cAMP-dependent protein kinase inhibitor beta, is a member of the cAMP-dependent protein kinase inhibitor family. (
  • Extremely potent competitive inhibitor of cAMP-dependent protein kinase activity, this protein interacts with the catalytic subunit of the enzyme after the cAMP-induced dissociation of its regulatory chains. (
  • We have previously reported that exposure of workers to benzene and to benzene metabolite hydroquinone in cultured cells induced DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to mediate the cellular response to DNA double strand break (DSB) caused by DNA-damaging metabolites. (
  • DNA-PK is a trimeric protein complex composed of a protein kinase, a DNA-PK catalytic subunit, and a DNA targeting heterodimer Ku70 and Ku80 ( 3 , 4 ). (
  • Because DNA-PK knockout and SCID mutant cell lines are viable, we reasoned that selective small molecule DNA-PK catalytic subunit inhibitors must sensitize cells to DSB-inducing treatments yet be nontoxic in the absence of DSBs ( 21 -23 ). (
  • The core NHEJ machinery consists of the Ku70/80 heterodimer and the catalytic subunit of DNA-dependent protein kinase (DNA-PK CS ), which together make the active DNA-PK, XRCC4, ligase IV, and the endonuclease artemis. (
  • PKI is a small, heat-stable protein with high affinity for the catalytic subunit of PKA, and binding of PKI to the catalytic subunit inhibits its activity ( 15 , 23 ). (
  • We have now designed and characterized a number of PKR mutants encoding proteins that retain their catalytic competence but are mutated in their regulatory double-stranded RNA (dsRNA) binding domains (RBDs). (
  • This protein may interact with the catalytic subunit of cAMP-dependent protein kinase and act as a competitive inhibitor. (
  • Aurora-B is the catalytic component of the chromosomal passenger complex (CPC), which is composed of three additional non-catalytic subunits that direct its activity: survivin, inner centromere protein (INCENP) and borealin. (
  • The compounds KT 5720, Rottlerin and quercetin were found to inhibit many protein kinases, sometimes much more potently than their presumed targets, and conclusions drawn from their use in cell-based experiments are likely to be erroneous. (
  • however, identification of pathological TAR DNA-binding protein 43 (TDP-43) as the hallmark lesion in sporadic ALS suggests new therapeutic targets for pharmacological intervention. (
  • The ability to determine structure-activity relationships (SAR) and identify cellular targets from cell lysates and tissues is of great utility for kinase inhibitor drug discovery. (
  • Stringent selection criteria for target identification were applied to deduce 28 protein targets for dasatinib and 31 protein targets for our general type II kinase inhibitor in HeLa cell lysate. (
  • Additional kinase and protein targets were identified with the general type II inhibitor analogs, with small structural changes leading to divergent target profiles. (
  • Our rapid workflow profiled cellular targets for six small molecules within a week, demonstrating that an unbiased proteomics screen of cellular targets yields valuable SAR information and may be incorporated at an early stage in kinase inhibitor development. (
  • Receptor Tyrosine Kinases as Targets for Drug Intervention", DN&P 7(6):334-339, 1994. (
  • Protein kinases are one of the most important categories of targets in oncology and drug discovery in today's research because of their pivotal roles in regulating cellular growth and survival. (
  • We have synthesized analogues of these compounds, identifying more selective sirtuin inhibitors and more potent calmodulin-dependent protein kinase inhibitors.The sirtuins are a family of NAD+-dependent deacetylases that regulate cellular aging and gene silencing in simple organisms and appear to play important regulatory roles in human cells that make them attractive anti-cancer targets. (
  • Many of these lipid messengers can activate protein kinase C (PKC) isozymes of which one function is to perpetuate the extracellular signals to the nucleus by phosphorylating other targets proteins. (
  • Inhibitors have been employed in vitro to identify protein targets and mechanism of action of SAPKs/MAPKs. (
  • CDK4 is a subunit of the protein kinase complex that is important for cell cycle G1 phase progression. (
  • Development of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) inhibitors with potent anti-toxoplasma activity. (
  • Proliferation of T. gondii is dependent on its ability to invade host cells, which is mediated in part by calcium-dependent protein kinase 1 (CDPK1). (
  • The present invention relates to compounds of the Formula I, the pharmaceutically acceptable salts and stereoisomers thereof, which inhibit, regulate and/or modulate tyrosine kinase signal transduction, compositions which contain these compounds, and methods of using them to treat tyrosine kinase-dependent. (
  • LY 294002 was found to inhibit casein kinase-2 with similar potency to phosphoinositide (phosphatidylinositol) 3-kinase. (
  • These potent TgCDPK1 inhibitors do not inhibit the growth of human cell lines and represent promising candidates as toxoplasmosis therapeutics. (
  • RKIP has also been shown to inhibit G protein coupled receptor kinases (GRK) when phosphorylated by protein kinase C. Via this mechanism it has been shown to exert beneficial effects on cardiac structure and function. (
  • An important prediction of this hypothesis is that inhibitors of PKC should inhibit these phorbol ester-induced changes in bag cell neuronal excitability. (
  • The viridins ( 9 ), such as wortmannin and the quercitins, are natural product classes, the members of which inhibit both DNA-PK and closely related phosphatidylinositol 3-kinases ( 10 ). (
  • Ibrutinib is a small-molecule inhibitor of Bruton's tyrosine kinase (BTK), the first drug in this class, and has been shown in preclinical studies to effectively inhibit malignant B-cell proliferation and survival in vivo . (
  • The MCP compounds were identified as inhibitors of Ras-Raf interactions and previously shown to inhibit multiple Ras-dependent transformation phenotypes when used as monoagents in cell culture analyses. (
  • We have investigated two structurally unrelated PI 3-kinase inhibitors, wortmannin and LY294002, to determine whether they inhibit DNA-PK and increase cellular radiosensitivity. (
  • Therefore, PI 3-kinase inhibitors may represent a new class of radiosensitizers that inhibit the repair of DNA damage. (
  • A group of extracellular-signal regulated protein kinase (ERK) inhibitors has been constructed based almost exclusively on their ability to inhibit the ERK activation cascade. (
  • Protein Kinases thus form a very critical component of cellular signal transduction networks controlling nearly every aspect of cellular function from cell division to apoptosis. (
  • In this study, we used a new, small molecule, a selective inhibitor of DNA-PKcs, 2-(morpholin-4-yl)-benzo[h]chomen-4-one (NU7026), as a probe to analyze the molecular events and pathways in hydroquinone-induced DNA DSB repair and apoptosis. (
  • Lastly, hydroquinone and NU7026 exhibited synergistic effects on promoting apoptosis by increasing the protein levels of pro-apoptotic proteins Bax and caspase-3 but decreasing the protein expression of anti-apoptotic protein Bcl-2. (
  • Survivin is usually a member in the inhibitors of apoptosis household. (
  • A number of mutations have been detected in CNS tumour cells, including genes involved in apoptosis and kinase-coding genes that play an important role in vital cellular functions such as viability, differentiation and proliferation. (
  • Small molecule inhibitors of the human sirtuins and calmodulin-dependent protein kinases have shown promising anti-cancer activity in cell-based screens and animal models. (
  • Therefore, protein kinase small molecule inhibitors (PKI) have been considered as promising novel agents for the treatment of thyroid carcinoma. (
  • MEK1 and 2 are downstream of genes frequently mutated in tumors (such as EGFR, RAS and RAF), and in preclinical models, MEK inhibitors have demonstrated potent antitumor activity. (
  • Epidermal growth factor receptor (EGFR) inhibitors are a new group of medicines developed to treat a wide range of cancers. (
  • Although effective in the treatment of many cancers, EGFR inhibitors often result in adverse reactions in the skin, which occur in at least half of treated patients. (
  • Some EGFR inhibitors are also protein kinase inhibitors. (
  • EGFR inhibitors are targeted specifically against EGFR on the outside of the cell. (
  • EGFR and kinase inhibitors may be particularly useful in cancer therapy as they are less toxic than more traditional chemotherapies. (
  • What are the cutaneous side effects of monoclonal antibody EGFR inhibitors? (
  • The i ncidence and severity of the EGFR inhibitor -induced follicular reactions are reduced by half by pre-treating with doxycycline or minocycline. (
  • Aortic contraction by OVA was significantly blocked not only by Rho kinase inhibitors Y-27632 and hydroxyfasudil, but also by Src inhibitors PP2 and Src inhibitor No. 5 and the EGFR inhibitors AG1478 and EGFR inhibitor 1. (
  • These results suggest that OVA-induced vasocontraction is mediated by the Rho-kinase-dependent inactivation of myosin light chain phosphatase via signaling downstream of Src-induced transactivation of EGFR. (
  • This peptide is an inhibitor for tyrosine protein kinases such as EGFR and Src subfamily members (IC50 = 7.5 mM for pp60 v-src). (
  • Aberrant regulation of cell growth pathways is required for normal cells to become cancerous, and in many types of cancer, cell growth is driven by a group of enzymes known as receptor tyrosine kinases (RTKs). (
  • Does anyone have any experience using PKC inhibitors (e.g., staurosporine, calphostin C, HA-1077) or protein phosphatase inhibitors (e.g., okadaic acid, calyculin A) on C. elegans in vivo? (
  • First, the effects of two purported PKC inhibitors, staurosporine (stauro) and H-7 [1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride], were examined on contractility of isolated, intact canine femoral artery. (
  • The effect of the protein kinase C (PKC) inhibitor staurosporine (ST) on the chemosensitivity of normal (colony-forming unit granulocyte-macrophage [CFU-GM]) and leukemic (acute myeloid leukemia-CFU [AML-CFU]) myeloid progenitors to daunorubicin (DNR) was evaluated. (
  • Tamaoki T, Nemoto H, Takahashi I, Kato Y, Murimoto M and Tomita F: Staurosporine, a potent inhibitor of phospholipid/Ca 2++ dependent protein kinase. (
  • Their findings reveal new insights into the structural regulation of TRIB proteins and show that these proteins, which are implicated in leukemia and other cancers, can bind to clinically approved kinase inhibitors. (
  • A protein kinase inhibitor is a type of enzyme inhibitor that blocks the action of one or more protein kinases. (
  • A protein kinase inhibitor is an enzyme inhibitor that blocks the action of protein kinases. (
  • Some of the kinase inhibitors used in treating cancer are inhibitors of tyrosine kinases. (
  • MAP Kinsases), Tyrosine Kinases (the Insulin Receptor), Histidine Kinases (common in Prokaryotes). (
  • We have engineered mammalian cell lines to identify and evaluate activators and inhibitors of PKC-dependent and independent signal transduction pathways. (
  • Houslay MD: Crosstalk: a pivotal role for protein kinase C modulating relationships between signal transduction pathways. (
  • Jones RE, Defeo-Jones D, McAvoy EM, Vuocolo GA, Wegrzyn RJ, Haskell KM and Oliff A: Mammalian cell lines engineered to identify inhibitors of specific signal transduction pathways. (
  • Lipid rafts are detergent-resistant, cholesterol and glycosphingolipid-enriched membrane domains which contain proteins that contribute to signal transduction ( 6 ). (
  • It is believed that tumour progression is related to various intracellular signal transduction pathways that involve the activation of protein kinases [29], including casein kinase (CK2). (
  • Protein kinases are versatile molecule switches that govern functional processes in signal transduction networks and regulate fundamental biological processes of cell cycle and organism development. (
  • Many pathogenic bacteria utilize two-component systems consisting of a histidine protein kinase (HPK) and a response regulator (RR) for signal transduction. (
  • Protein Kinase C (PKC) is a component of signal transduction system mediating a variety of cellular activities including malignant transformation PKC activity is reportedly elevated in neoplasms including malignant brain tumors. (
  • These results show that myr-psi PKC is a selective and cell-permeable inhibitor of PKC. (
  • The InhibitorSelect™ 96-Well Protein Kinase Inhibitor Library II consists of 80, well-characterized, cell permeable, potent and reversible protein kinase inhibitors. (
  • Inhibits the kinase activity of CDK2 bound to cyclin A, but has little inhibitory activity on CDK2 bound to SPDYA (PubMed:28666995). (
  • CDKN1B inhibits the kinase activity of CDK2 through conformational rearrangements. (
  • We have now found that treatment of bag cell neurons with the protein kinase inhibitor 1-[5- isoquinolinesulfonyl]-2-methyl piperazine (H-7) inhibits the phorbol ester-induced enhancement of bag cell action potentials and prevents the enhancement of calcium current by phorbol esters. (
  • A representative of this class, 1-(2-hydroxy-4-morpholin-4-yl-phenyl)-ethanone, inhibits the DNA-dependent protein kinase (DNA-PK) and differs significantly from previously studied DNA-PK inhibitors both structurally and functionally. (
  • Also inhibits Ca 2+ /calmodulin-dependent protein kinase II, casein kinase I and myosin light chain kinase. (
  • In our previous studies we showed antitumor and anti-inflammatory activities of protein kinases inhibitor pyrrol derivate 1-(4-Cl-benzyl)-3-Cl-4-(CF3-fenylamino)-1H-pyrrol-2,5-dione (MI-1) on rat colon cancer model. (
  • The obtained antitumor effects of CK2 inhibitors significantly exceeded their mild or no effect on normal astrocytes in control, which supports the therapeutic potential of these compounds against gliomas. (
  • The aims of this study are to investigate the antitumor function of PKC inhibitors against malignant glial tumors prior to clinical application, and further to examine the effects of PKC inhibitors in combination with cytokines such as TNF and IFN,and analyze the underlying molecular biological mechanisms. (
  • Cyclin-dependent kinase 4 inhibitor D (CDKN2D) is a specific inhibitor of cyclin-dependent kinases CDK4 and CDK6. (
  • Alternative strategies, such as targeting other kinases in the cascade or development of allosteric inhibitors have been proposed. (
  • For these reasons, strategies to rationally design chemotherapeutic agents that specifically antagonize the Ras/Raf/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling cascade have been considered to be promising ( 6 ). (
  • We investigated the role of protein kinase C θ (PKCθ) in the activation of the NF-κB cascade in primary human CD4 + lymphocytes. (
  • Mitogen Activated Protein Kinase Kinase 2 inhibitors - Pipeline Insight, 2021," report provides comprehensive insights about 10+ companies and 10+ pipeline drugs in Mitogen Activated Protein Kinase Kinase 2 inhibitors pipeline landscape. (
  • The companies and academics are working to assess challenges and seek opportunities that could influence Mitogen Activated Protein Kinase Kinase 2 inhibitors R&D. The therapies under development are focused on novel approaches for Mitogen Activated Protein Kinase Kinase 2 inhibitors. (
  • This segment of the Mitogen Activated Protein Kinase Kinase 2 inhibitors report encloses its detailed analysis of various drugs in different stages of clinical development, including phase III, II, I, preclinical and Discovery. (
  • Koselugo (selumetinib) is inhibitor of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2). (
  • 10+ key companies which are developing the Mitogen Activated Protein Kinase Kinase 2 inhibitors. (
  • The companies which have their Mitogen Activated Protein Kinase Kinase 2 inhibitors drug candidates in the most advanced stage, i.e. phase III include, Astrazeneca. (
  • Mitogen Activated Protein Kinase Kinase 2 inhibitors pipeline report provides the therapeutic assessment of the pipeline drugs by the Route of Administration. (
  • Mitogen activated protein kinase inhibitors: where are we now and where are we going? (
  • The mitogen activated protein (MAP) kinases are especially attractive because they regulate both cytokine production and cytokine action. (
  • We reported that the mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor U0126 inhibited anchorage-independent growth of Ki- ras -transformed rat fibroblasts by simultaneously blocking both extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR)-p70 S6K pathways. (
  • These cascades appear to be functionally linked through the action of a mitogen-activated protein kinase kinase kinase (MAPKKK), MEKK1, which induces JNK as well as inhibitor of κB factor (IκB) kinase (IKK)β activity during CD28 coligation ( 7 , 8 , 9 , 10 ). (
  • In the present in vivo study, we have investigated whether inhibitors of the Na + /Mg 2+ exchanger quinidine and imipramine influence the development of hypertension and whether this is associated with modulation of mitogen-activated protein (MAP) kinase activation in arteries and kidneys of hypertensive rats. (
  • C. J. Malemud, " Small Molecular Weight Inhibitors of Stress-Activated and Mitogen- Activated Protein Kinases", Mini-Reviews in Medicinal Chemistry (2006) 6: 689. (
  • To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer. (
  • the interaction is required for cyclin D and CDK4 complex assembly, induces nuclear translocation and activates the CDK4 kinase activity. (
  • Such knowledge will be of considerable value in protein modeling, ligand design, and structure-activity analysis. (
  • The p38 MAP Kinase Inhibitor X, BIRB 796, also referenced under CAS 285983-48-4, controls the biological activity of p38 MAP Kinase. (
  • an index of Rho-kinase activity) in vascular smooth muscle cells (VSMCs). (
  • Increased protein kinase C (PKC) activity has been implicated in the pathogenesis of diabetic retinopathy and nephropathy. (
  • In an effort to identify additional CaMK inhibitors that exhibit more potent activity in triggering leukemia cell differentiation, we synthesized 45 analogues of KN-62 and determined their ability to induce HL-60 cell differentiation. (
  • We have compared two different methods of attenuating protein kinase C (PKC) activity in vascular smooth muscle. (
  • The Asp-Phe-Gly (DFG) motif plays an important role in the regulation of kinase activity. (
  • Hallam TJ: Functional significance of protein kinase C in human T cell activity: a new therapeutic class? (
  • Wortmannin and LY294002 inhibited the kinase activity of purified DNA-PK and inactivated cellular DNA-PK kinase activity. (
  • Quinidine and imipramine attenuated the development of hypertension and normalized MAP kinase activity. (
  • Calcium/Calmodulin-Dependent Protein Kinase IV Suppresses IL-2 Production and Regulatory T Cell Activity in Lupus. (
  • In summary, the results suggest that protein kinase inhibitor alpha is a promising gene candidate to partially rescue physical activity in the polygenic model of low voluntary running. (
  • To characterize in more detail the relationships between kinase activity and junction organization, we have studied the effects of the protein kinase C agonist phorbol myristate acetate (PMA) on the intracellular localization of cingulin, E-cadherin, desmoplakin and actin microfilaments in confluent MDCK monolayers. (
  • The gene splicing converted a protein with 70 amino acids into one of 109 amino acids, and did not change the inhibitory potency to PKA, but changed it from a protein that had no detectable PKG inhibitory activity to one that now inhibited PKG in the nanomolar range. (
  • The Cyclin-Dependent Protein Kinase Inhibitor Set controls the biological activity of Cyclin-Dependent Protein Kinase. (
  • Barasertib-hQPA is a highly selective inhibitor of aurora-B kinase that has shown tumouricidal activity against a range tumour cell lines including those of leukaemic AML origin. (
  • Calcium/calmodulin-dependent protein kinase IV (CaMK4) is expressed at increased levels in T cells from SLE patients (4) and lupus-prone mice (5). (
  • In conclusion, NU7441 shows sufficient proof of principle through in vitro and in vivo chemosensitization and radiosensitization to justify further development of DNA-PK inhibitors for clinical use. (
  • In the present study we investigated the effects of small molecule CK2 inhibitors on proliferation and viability of glioma cells in vitro. (
  • We present the effects of two novel bumped kinase inhibitors, BKI-1517 and BKI-1553, against Neospora caninum tachyzoites in vitro and in experimentally infected pregnant mice. (
  • Synthetic peptides corresponding to the pseudosubstrate domains of protein kinase C (PKC) have been used as specific inhibitors of PKC in in vitro assays and permeabilized cell systems. (
  • Development and application of specific inhibitors for cyclin-dependent protein kinases on the basis of their substrate specificities. (
  • A protein kinase C-beta-selective inhibitor ameliorates neural dysfunction in streptozotocin-induced diabetic rats. (
  • is a selective inhibitor of PKC beta. (
  • We have developed ATP competitive inhibitors of TgCDPK1 that block invasion of parasites into host cells, preventing their proliferation. (
  • Protein kinases are enzymes within the cell that result in cellular proliferation. (
  • Protein kinase inhibitors reduce cell proliferation. (
  • Bone morphogenetic protein (BMPs) have diverse and important functions in the proliferation and differentiation of adult stem cells inside our tissues. (
  • Outcomes Recombinant BMP2, noggin, and BMPR1a-ECD proteins creation Recombinant BMP2 and noggin had been purified from the released protocols (13, 14) (Fig. 1A, B). Recombinant BMPR1a-ECD is usually itself not really well folded and it is unstable when indicated in and data possess backed that endogenous BMP2 is enough to repress the proliferation of pores and skin stem cells in hair roots. (
  • Structural and biochemical studies of the genetic and molecular determinants of protein kinases binding with inhibitors have been the cornerstone of drug discovery efforts in clinical oncology leading to proliferation of effective anticancer therapies. (
  • We have hypothesized that this effect is mediated by the activation of protein kinase C (PKC). (
  • Over the last several years, evidence has accumulated that implicates the hyperglycemia-induced activation of protein kinase C (PKC 1 ) as one of the mechanisms responsible for the development and/or progression of chronic complications of diabetes. (
  • Aurora kinases play an essential role in orchestrating chromosome alignment, segregation and cytokinesis during mitotic progression, with both aurora-A and B frequently over-expressed in a variety of human malignancies. (
  • The A31 mouse fibroblast cell line, has been stably transfected with a construct containing a triplet repeat of the TPA response element (TRE) upstream of a thymidine kinase promoter fused to the human growth hormone (hGH) gene. (
  • Members of the phosphatidylinositol (PI) 3-kinase gene family, including the ataxia telangiectasia gene and the DNA-dependent protein kinase (DNA-PK), are involved in regulating cellular radiosensitivity. (
  • Next, nucleus accumbens injections of an adenoviral-associated virus that overexpressed the protein kinase inhibitor alpha gene increased running distance in low voluntary running, but not wild-type rats. (
  • We have now demonstrated that the switch from a cAMP-dependent protein kinase (PKA)-specific inhibitor to one with dual specificity arises as a consequence of alternate gene splicing. (
  • Indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress the human epidermal receptor type 2 (HER2) protein and who have received prior therapy including an anthracycline, a taxane, and trastuzuma. (
  • On binding with an epidermal growth factor ligand outside the cell, they activate a protein kinase inside the cell. (
  • By combining a simplified affinity enrichment and on-bead protein digestion workflow with quantitative proteomics, we achieved sensitive and specific enrichment of target kinases using our small molecule probes. (
  • The aims of this volume are to highlight the tremendous pharmacological potential of protein kinase and protein phosphatase inhibitors, to provide a thorough overview of the most remarkable achievements in the field and to illustrate how beneficial these studies can be for the advancement of both basic knowledge on biological regulation and deregulation and for the clinical treatment of a wide spectrum of diseases. (
  • Molecular Dynamics of Protein Kinase-Inhibitor Complexes: A Valid. (
  • Atomistic molecular dynamics (MD) simulations present a convenient way to study PK-inhibitor complexes and have been increasingly used in recent years in structure-based drug design. (
  • That enables them to follow and understand structure and dynamics of protein-ligand systems with extreme molecular detail on scales where motion of individual atoms can be tracked. (
  • Heat shock protein 90 is really a molecular chaperone that assists the correct folding and stabilization of many proteins in cells. (
  • Though Hsp90 can be a molecular chaperone that assists the correct folding of many proteins in cells, it doesn't bind to unfolded survivin. (
  • Nishizuka Y: The molecular heterogeneity of protein kinase C and its implications for cellular regulation. (
  • Endogenous mRNA levels for protein kinase inhibitor alpha, dopamine receptor D1, dopamine receptor D2, and Fos were all only lower in wild-type rats following overexpression compared to low voluntary runners, suggesting a potential molecular and behavioral resistance in wild-type rats. (
  • Importantly, there were divergent molecular responses to protein kinase inhibitor alpha overexpression in low voluntary runners compared to wild-type rats. (
  • Consequently, brain penetrant specific CK-1 inhibitors may provide a new therapeutic strategy for treating ALS and other TDP-43 proteinopathies. (
  • Traxler, Protein Tyrosine Kinase Inhibitors in Cancer Treatment, Expert Opinion on Therapeutic Patents, 7(6):571-588, 1997. (
  • Cancer stemness plays critical roles in tumor aggressiveness and therapeutic resistance, and dipeptidyl peptidase IV (DPP4) has been recently identified as a cancer stemness-related protein. (
  • We investigated the therapeutic use of a potent, specific DNA-PK inhibitor (NU7441) in models of human cancer. (
  • For this reason, targeting hsp90 provides therapeutic advantages more than other target-therapies as several Hsp90-related oncogenic proteins is often targeted simultaneously. (
  • While it is actually broadly believed that Hsp90 inhibitors induce cancer cell death by indirect down-regulation of survivin as one among its a number of therapeutic functions, a research demonstrated that 17-AAG remedy slightly enhanced the amount of survivin current from the human DU145 prostate cancer cells. (
  • Inhibitors of MEK-ERK and mTOR-p70 S6K pathways may provide a therapeutic strategy to selectively target neoplasms proliferating at ectopic locations, with acceptable effects on normal cells in their proper tissue context. (
  • An important clinical task is to coherently integrate the use of protein-targeted drugs into preexisting therapeutic regimens, with the goal of improving treatment efficacy. (
  • Bradshaw D, Hill CH, Nixon JS and Wilkinson SE: Therapeutic potential of Protein Kinase C inhibitors. (
  • For example, the G1/S transition is regulated by Cdk2/cyclin E, Cdk3/unknown cyclin, Cdk4/cyclin D1-3, Cdk6/cyclin D1, and Cdk8/cyclin C. The frequent deregulation of Cdks and their regulators in cancer has stimulated the search for potent and selective inhibitors of Cdks for both research and therapeutic use. (
  • Treatment with NU7026 did not alter the production of reactive oxygen species and oxidative stress by hydroquinone but repressed the protein level of DNA-PKcs and blocked the induction of the kinase mRNA and protein expression by hydroquinone. (
  • 1989 ). ZO-1 mRNA and protein expression during tight junction assembly in Caco-2 cells. (
  • Protein kinases are enzymes that add a phosphate (PO4) group to a protein, and can modulate its function. (
  • Protein Kinases are enzymes which catalyze the addition of a phosphate (PO43-) group to a substrate protein. (
  • PKCs are curiously versatile enzymes in the sense that they can not only function as kinases but also as phosphatases and ATPases. (
  • There are also protein kinases that phosphorylate other amino acids, including histidine kinases that phosphorylate histidine residues. (
  • DNA-PK has been shown to phosphorylate several cellular proteins in vivo , including itself and the variant histone H2AX ( 15 ). (
  • Activated IKKs phosphorylate the inhibitory proteins, IκBα and IκBβ, leading to their degradation and release of NF-κB transcription factors into the nucleus ( 8 , 14 , 15 ). (
  • In contrast to previously studied DNA-PK inhibitors, these compounds appear benign, exhibiting no toxic effects in the absence of DSB-inducing treatments. (
  • In the present work, representative compounds from the six different series of inhibitors were analyzed for their effects on membrane integrity and macromolecular synthesis. (
  • Although the hydrogen bond is known to be an important mediator of intermolecular interactions, there has yet to be an analysis of the role of CH...O hydrogen bonds in protein-ligand complexes. (
  • CH groups adjacent to the positively charged nitrogen of nicotinamide exhibit geometric preferences strongly suggestive of hydrogen bonding interactions, as do heterocyclic CH groups in kinase ligands, while other aromatic CH groups do not exhibit these characteristics. (
  • Ab initio calculations reveal a considerable range of CH...O hydrogen bonding potentials among different aromatic ring systems, with nicotinamide and heterocycles preferred in kinase inhibitors showing particularly favorable interactions. (
  • These results provide compelling evidence for the existence of CH...O hydrogen bonds in protein-ligand interactions, as well as information on the relative strength of various aromatic CH donors. (
  • Two studies explored the structures and protein interactions of the pseudokinases TRIB1 (Jamieson et al . (
  • The continuous growth of biological information and a remarkable breath of structural, genetic, and pharmacological studies on protein kinase genes have significantly advanced our knowledge of the kinase activation, drug binding and allosteric mechanisms underlying kinase regulation and interactions in signaling cascades. (
  • cdkn2d has direct interactions with proteins and molecules. (
  • Recent findings suggest that protein kinase C (PKC) regulates the persistence of long-term potentiation (LTP). (
  • The Raf kinase inhibitor protein (RKIP) is a kinase inhibitor protein, that regulates many signaling pathways within the cell. (
  • Similarly, ALDH1, a protein that positively regulates stem cells shows mild expression in low grade cervical tumour, but positive signals are more amplified in an aggressive stage of tumour condition when compared with Sox2. (
  • The expression study with RKIP, a protein that negatively regulates stem cells, interestingly defines the higher expression in low grade cervical cancer to regulate the tumour, but shows little or no very mild expression in the aggressive stage of tumour. (
  • Thyroid cancer is frequently associated to the oncogenic conversion of protein kinases such as RET (medullary thyroid cancer) and BRAF (papillary and undifferentiated thyroid cancer). (
  • Crizotinib is used for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic-lymphoma kinase (ALK)-positive as detected by a FDA-approved test. (
  • Ceritinib is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. (
  • Kinase inhibitors such as dasatinib are often used in the treatment of cancer and inflammation. (
  • however, drugs that target RTKs, known as tyrosine kinase inhibitors (TKIs) have not been effective in treating breast cancer. (
  • We find that these new kinase inhibitors meet these criteria and have potential as a new cancer therapy. (
  • Missense mutations in ATM kinase, a master regulator of DNA damage responses, are found in many cancers, but their impact on ATM function and implications for cancer therapy are largely unknown. (
  • Here we report that 72% of cancer-associated ATM mutations are missense mutations that are enriched around the kinase domain. (
  • Moreover, scientific studies showed that Hsp90 stabilizes different vital oncogenic proteins such as survivin, Akt, Erb-2 and HIF-1 in cancer cells. (
  • Several research have investigated the probability of focusing on survivin utilizing Hsp90 inhibitors, determined by the fact that survivin is significant for cancer survival and progression. (
  • We also hypothesize the use of Hsp90 inhibitors could possibly not have the capacity to down-regulate survivin expression in specified cancer cells. (
  • Recent advances in understanding allosteric regulation of protein kinases have fueled unprecedented efforts aiming in the discovery of targeted and allosteric kinase inhibitors that can combat cancer mutants and are at the forefront of the precision medicine initiative in oncology. (
  • To determine the differences in response following the use of aldehyde dehydrogenase 1 (ALDH1) and Raf kinase inhibitor protein (RKIP) as cervical cancer stem cell markers. (
  • Because they are so integral to so many key cell functions, a disease like cancer (characterized by abnormal cell growth) relies heavily on protein kinases to survive and spread. (
  • LKT Laboratories carries hundreds of protein kinase inhibitors for use in the research of protein and cell functions, especially as they pertain to cancer, autoimmune disorders, cardiac disease, and other conditions. (
  • Over-expression of the ABC drug transporter proteins P-glycoprotein (Pgp) and Breast cancer resistance protein (BCRP) is a major obstacle for chemotherapy in many tumour types with Pgp conferring particularly poor prognosis in acute myeloid leukaemia (AML). (
  • Orthovanadate (OVA), a protein tyrosine phosphatase (PTPase) inhibitor, exerts contractile effects on smooth muscle in a Rho-kinase-dependent manner, but the precise mechanisms are not elucidated. (
  • In this review, we focused on structural, biochemical and computational studies of the ErbB and BRAF kinases and discuss how diversity of the structural landscape for these kinase genes and dimerization- dependent mechanisms of their regulation can be leveraged in the design and discovery of kinase inhibitors and allosteric modulators of kinase activation. (
  • 3) PKC inhibitors plus TNF and/or IFN exerted synergistic or additive anti-tumor effects on human glioma cells, via mechanisms of enhancing the expression of the cytokine receptors on the tumor cells. (
  • Effects of pentoxifylline and protein kinase C inhibitor on phorbol ester-induced intercellular adhesion molecule-1 expression in brain microvascular endothelial cells. (
  • Effects of pentoxifylline and protein kinase C inhibitor on phorbol ester-induced intercellular adhesion molecule-1. (
  • These results gave useful information for developing spesific substrates and competitive inhibitors for each kinase. (
  • To obtain substrates/inhibitors which are resistant to enzymatic proteolysis, we undertook a synthesis of cyclic or retro-inverso peptides. (
  • RKIP is a member of the phosphatidylethanolamine-binding protein family and has displayed disruptive regulation on the Raf-1-MEK1/2, ERK1/2 and NF-kappaB signalling pathways, by interaction with the Raf-1 kinase. (
  • To study the biochemical basis for induction of anoikis sensitivity, we examined the effects of the MEK inhibitors on ERK and p70 S6K pathways in anchored versus nonanchored cells. (
  • Although different tumor types rely to differing degrees on activation of the Raf, phosphatidylinositol 3-kinase, and Ral guanine nucleotide exchange factor effector pathways ( 5 ), the particular importance of Raf activation has long been appreciated ( 6 ). (
  • LKT's broad selection of inhibitors target many different signaling pathways. (
  • The human genome contains ~ 500 protein kinase genes constituting a whopping 2% of the total number of human genes. (
  • The protein kinase inhibitor (PKI) family includes three genes encoding small, heat-stable inhibitors of the cyclic AMP-dependent kinase PKA. (
  • We have confirmed using bacterially produced pure protein that a single inhibitor species has dual specificity for both PKA and cGMP-dependent protein kinase (PKG), inhibiting each with very high and closely similar inhibitory potencies. (
  • Moreover, MS-275 and SAHA suppressed granulocyte chemotactic protein-2 (GCP-2), monocyte chemotactic protein-2 (MCP-2) and macrophage migration inhibitory factor (MIF) in E11 cells in a concentration-dependent manner. (
  • instead, pseudokinases typically function as scaffolds, often promoting the degradation of substrate proteins by bringing them into close proximity with ubiquitin ligases. (
  • Cdc2 kinase or cdk5, a member of cyclin-dependent protein kinases, phosphorylates a Ser/Thr site immediately followed by a proline which acts as the substrate specificity determinant. (
  • We have examined structural features of proline which are essential for the substrate recognition by the kinase and found that the pyrrolidine ring of proline is primarily important. (
  • Publications] Ando, S.: 'Role of the pyrrolidine ring of proline in determining the substrate specificity of cdc2 kinase or cdk5' J.Biochem.122. (
  • Tyrosine kinase inhibitors (TKIs) are used as targeted drugs for advanced renal cell carcinoma (RCC), although most cases eventually progress by acquiring resistance. (
  • Fig. 6: DPP4 inhibitor therapy potentially improves prognosis and tumor regression of renal cell carcinoma (RCC) patients treated with tyrosine kinase inhibitors (TKIs). (
  • Checkpoint Inhibitors for the Treatment of Renal Cell Carcinoma. (
  • In a phase 2 multicenter study, sotrastaurin, a protein kinase C inhibitor, has shown promise in preserving renal graft function but lacks potency as an immunosuppressive agent. (
  • In previous studies we have shown that protein kinase inhibitors and extracellular calcium can affect dramatically the assembly of tight junctions (TJ) and the localization of the TJ protein cingulin at sites of cell-cell contact in renal epithelial (MDCK) cells. (