• cyclin-depende
  • Cyclin-dependent kinases (CDKs) and their regulators show frequent abnormalities in tumors. (aacrjournals.org)
  • Since their initial discovery in yeast ( 1 ) and the identification of a first homologue in man ( 2 ), cyclin-dependent kinases (CDK) have been the object of considerable work with the aim of understanding their regulatory mechanisms and functions in controlling the various steps of the cell division cycle ( 3 ). (aacrjournals.org)
  • The closest relatives of MAPKs are the cyclin-dependent kinases (CDKs). (wikipedia.org)
  • phosphatidylinositol 3-kina
  • We investigated the effect of 2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl} propanenitrile (NVP-BEZ235) (Novartis, Basel Switzerland), a dual phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor currently being tested in phase I clinical trials, in radiosensitization. (aspetjournals.org)
  • Many growth stimuli, such as insulin-like growth factor-1 (IGF-1), can bind to membrane-bound receptors that activate phosphatidylinositol-3-kinase (PI3K) and subsequently Akt ( 10 , 12 ). (physiology.org)
  • apoptosis
  • Cleavage of the C-terminal inhibitory domain by caspase-3 during apoptosis can also activate the kinase. (wikipedia.org)
  • The histone deacetylase inhibitors are a new class of cytostatic agents that inhibit the proliferation of tumor cells in culture and in vivo by inducing cell cycle arrest, differentiation and/or apoptosis. (wikipedia.org)
  • binds
  • Unfortunately, UCN-01 binds avidly to human plasma proteins, limiting bioavailability. (aacrjournals.org)
  • Since then crystallographic studies have revealed that imatinib binds to the kinase domain of Abl only when the domain adopts the inactive or "closed" conformation. (wikipedia.org)
  • The base that is often seen in compounds with selectivity for JAK3 are pyrrolopyrimidine as they bind to the same region of the JAKs as purine of the ATP binds. (wikipedia.org)
  • cellular
  • Identification of JAK3 inhibitor VI as a compound that efficiently abrogates ErbB2‐induced cellular invasion. (pubmedcentralcanada.ca)
  • SU6656 has been used primarily as a research tool to investigate the function of Src family kinases in cellular signal transduction processes and biology. (wikipedia.org)
  • Similar to the SAPK/JNK pathway, p38 MAP kinase is activated by a variety of cellular stresses including osmotic shock, inflammatory cytokines, lipopolysaccharides (LPS), Ultraviolet light, and growth factors. (wikipedia.org)
  • ROCK plays a role in a wide range of different cellular phenomena, as ROCK is a downstream effector protein of the small GTPase Rho, which is one of the major regulators of the cytoskeleton. (wikipedia.org)
  • Phosphorylation of proteins by kinases is an important mechanism in communicating signals within a cell (signal transduction) and regulating cellular activity, such as cell division. (wikipedia.org)
  • Cellular growth and reproduction may rely to some degree on tyrosine kinase. (wikipedia.org)
  • Furthermore, tyrosine kinase activity has been determined to be correlated to cellular transformation. (wikipedia.org)
  • A protein tyrosine kinase called pp125 is likely at hand in the influence of cellular focal adhesions, as indicated by an immunofluorescent localization of the said kinase. (wikipedia.org)
  • This tandem activation loop phosphorylation (that was proposed to be either distributive or processive, dependent on cellular environment) is performed by members of the Ste7 protein kinase family, also known as MAP2 kinases. (wikipedia.org)
  • An example of this is Decernotinib which showed 41-fold selectivity for JAK3 vs JAK1 in vitro enzyme assays while the selectivity for JAK3 was not maintained in cellular assays where it showed a slight preference for JAK1. (wikipedia.org)
  • signaling molecules
  • New forms of resistance can arise as: missense mutations within the Abl kinase domain, over-expression of Bcr-Abl, increased production of transmembrane plasma proteins, or the constitutive activation of downstream signaling molecules such as Src-family kinases. (wikipedia.org)
  • MAPKs
  • In contrast to the classical MAP kinases, these atypical MAPKs require only a single residue in their activation loops to be phosphorylated. (wikipedia.org)
  • As mentioned above, MAPKs typically form multi-tiered pathways, receiving input several levels above the actual MAP kinase. (wikipedia.org)
  • pathway
  • Activation of the Foxo pathway leads to expression of atrogene products Atrogin-1/MAFbx and MuRF-1, proteins that are integral to the development of muscle atrophy ( 5 , 19 , 26 ). (physiology.org)
  • Identification of the tuberous sclerosis complex‐2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3‐kinase/akt pathway. (currentprotocols.com)
  • Janus kinase 3 inhibitors work by inhibiting the action of the enzyme Janus Kinase 3 and therefore interferes with the JAK-STAT signaling pathway. (wikipedia.org)
  • subunit
  • I KACh is a heterotetrameric G-protein coupled inward rectifying K + channel (GIRK) composed of (GIRK1) 2 /(GIRK4) 2 subunits, activated in response to the binding of the βγ-subunit of the heterotrimeric G-protein, G i2 , which is released after the binding of ACh to the M 2 muscarinic receptor ( 7 , 8 ). (diabetesjournals.org)
  • imatinib
  • Due to increasing resistance and intolerance to imatinib efforts were made to develop new drugs that could inhibit the Bcr-Abl tyrosine kinase. (wikipedia.org)
  • While drug screening was used to develop imatinib, second generation TKI's were developed with rational drug design approach due to increased knowledge in structural biology of the Bcr-Abl tyrosine kinase. (wikipedia.org)
  • Imatinib (Gleevec) was discovered in 1992 and is regarded as first generation drug since it is the first Bcr-Abl tyrosine kinase inhibitor to be used in the treatment of CML. (wikipedia.org)
  • In the development of imatinib, the structure of Bcr-Abl tyrosine kinase played a limited role because it was unknown. (wikipedia.org)
  • At the time of its discovery, in the absence of structural information, no clear explanation for the impressive selectivity of imatinib could be found. (wikipedia.org)
  • CDKs
  • Ten low molecular weight pharmacologic inhibitors of CDKs are currently in clinical trials against various cancers, including the 2,6,9-trisubstituted purine ( R )-roscovitine (CYC202/Seliciclib). (aacrjournals.org)
  • CDKs have also been the targets of numerous molecular screening studies designed to identify low molecular weight pharmacologic inhibitors with potential use against various human diseases derived from abnormal cell cycle regulation (review in ref. 4 ). (aacrjournals.org)
  • enzyme
  • Two of the pyrrole carboxamides, PSI2106 and MDF2085, were especially notable in vitro inhibitors of recombinant human MKP-1 enzyme activity with IC 50 values of 8.0 ± 0.9 and 8.3 ± 0.8 μM, respectively. (aspetjournals.org)
  • Enzyme activity of ROCK1 is inhibited when the pleckstrin-homology and Rho-binding domains in the C-terminus independently bind to the N-terminus kinase domain. (wikipedia.org)
  • A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. (wikipedia.org)
  • HDIs should not be considered to act solely as enzyme inhibitors of HDACs. (wikipedia.org)
  • structurally
  • In particular, one class of p38 MAP kinase inhibitors, the pyridinyl imidazole derivatives, is intensely investigated by several industrial groups, but so far no studies concerning the metabolism of these structurally related substances seem to be available. (aspetjournals.org)
  • A number of structurally diverse histone deacetylase inhibitors have shown potent antitumor efficacy with little toxicity in vivo in animal models. (wikipedia.org)
  • novel
  • Our results further showed that JAK3 inhibitor VI function was independent of JAK kinases but involved downregulation of cathepsin L. We postulate that the screening method and the verification experiments that are based on oncogene‐induced changes in lysosomal hydrolase activity and lysosomal distribution could be used for identification of novel inhibitors of ErbB2‐induced invasiveness. (pubmedcentralcanada.ca)
  • Staurosporine is the precursor of the novel protein kinase inhibitor midostaurin (PKC412). (wikipedia.org)
  • GSK3
  • Treatment of atrial myocytes with the GSK3β inhibitor Kenpaullone increased levels of SREBP-1 and expression of GIRK4 and I KACh , whereas a dominant-active GSK3β mutant decreased SREBP-1 and GIRK4 expression. (diabetesjournals.org)
  • In Akita mice treated with GSK3β inhibitors Li + and/or CHIR-99021, Li + increased I KACh , and Li + and CHIR-99021 both partially reversed the decrease in HF fraction while increasing GIRK4 and SREBP-1 expression. (diabetesjournals.org)
  • regulators
  • Thus the role of mammalian ERK1/2 kinases as regulators of cell proliferation is not a generic, but a highly specialized function. (wikipedia.org)
  • staurosporine
  • Structural analysis of kinase pockets demonstrated that main chain atoms which are conserved in their relative positions to staurosporine contributes to staurosporine promiscuity. (wikipedia.org)
  • Thus
  • ERK3 (MAPK6) and ERK4 (MAPK4) were recently shown to be directly phosphorylated and thus activated by PAK kinases (related to other MAP3 kinases). (wikipedia.org)
  • Dehydrons cause "epistructural tension", that is, interfacial tension around the protein structure and thus promote protein-protein interactions and protein-ligand associations. (wikipedia.org)
  • Thus, dehydrons constitute effective selectivity filters for drug design, giving rise to so-called "wrapping technology", a platform to design safer drugs. (wikipedia.org)
  • clinical
  • Our data offer a rationale for combining NVP-BEZ235 along with an autophagy inhibitor (i.e., chloroquine) and radiation in future clinical trials. (aspetjournals.org)
  • Clinical trials in humans began in 2010, making CK-4945 the first CK2 inhibitor to reach this stage of drug development. (wikipedia.org)
  • gene
  • Bcr-Abl was regarded as highly attractive target for drug intervention since the Bcr-Abl fusion gene encodes a constitutively activated kinase. (wikipedia.org)
  • Signaling leads to phosphorylation and dimerization of the adaptor proteins STAT. When activated they translocate into the nucleus where they modulate gene transcription. (wikipedia.org)
  • HDAC inhibitors (HDI) block this action and can result in hyperacetylation of histones, thereby affecting gene expression. (wikipedia.org)