Amyloid Precursor Protein Secretases: Endopeptidases that are specific for AMYLOID PROTEIN PRECURSOR. Three secretase subtypes referred to as alpha, beta, and gamma have been identified based upon the region of amyloid protein precursor they cleave.Cyclic S-OxidesHuman papillomavirus 31: A type of ALPHAPAPILLOMAVIRUS associated with high risk for anogenital neoplasms.ThiadiazolesReceptors, Notch: A family of conserved cell surface receptors that contain EPIDERMAL GROWTH FACTOR repeats in their extracellular domain and ANKYRIN repeats in their cytoplasmic domains. The cytoplasmic domain of notch receptors is released upon ligand binding and translocates to the CELL NUCLEUS where it acts as transcription factor.Aspartic Acid Endopeptidases: A sub-subclass of endopeptidases that depend on an ASPARTIC ACID residue for their activity.Receptor, Notch1: A notch receptor that interacts with a variety of ligands and regulates SIGNAL TRANSDUCTION PATHWAYS for multiple cellular processes. It is widely expressed during EMBRYOGENESIS and is essential for EMBRYONIC DEVELOPMENT.Leukemia, Prolymphocytic: A chronic leukemia characterized by a large number of circulating prolymphocytes. It can arise spontaneously or as a consequence of transformation of CHRONIC LYMPHOCYTIC LEUKEMIA.Endopeptidases: A subclass of PEPTIDE HYDROLASES that catalyze the internal cleavage of PEPTIDES or PROTEINS.Azirines: Unsaturated azacyclopropane compounds that are three-membered heterocycles of a nitrogen and two carbon atoms.Amyloid beta-Protein Precursor: A single-pass type I membrane protein. It is cleaved by AMYLOID PRECURSOR PROTEIN SECRETASES to produce peptides of varying amino acid lengths. A 39-42 amino acid peptide, AMYLOID BETA-PEPTIDES is a principal component of the extracellular amyloid in SENILE PLAQUES.Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (ENDOPEPTIDASES).Ganglioglioma: Rare indolent tumors comprised of neoplastic glial and neuronal cells which occur primarily in children and young adults. Benign lesions tend to be associated with long survival unless the tumor degenerates into a histologically malignant form. They tend to occur in the optic nerve and white matter of the brain and spinal cord.Amyloid beta-Peptides: Peptides generated from AMYLOID BETA-PEPTIDES PRECURSOR. An amyloid fibrillar form of these peptides is the major component of amyloid plaques found in individuals with Alzheimer's disease and in aged individuals with trisomy 21 (DOWN SYNDROME). The peptide is found predominantly in the nervous system, but there have been reports of its presence in non-neural tissue.Alzheimer Disease: A degenerative disease of the BRAIN characterized by the insidious onset of DEMENTIA. Impairment of MEMORY, judgment, attention span, and problem solving skills are followed by severe APRAXIAS and a global loss of cognitive abilities. The condition primarily occurs after age 60, and is marked pathologically by severe cortical atrophy and the triad of SENILE PLAQUES; NEUROFIBRILLARY TANGLES; and NEUROPIL THREADS. (From Adams et al., Principles of Neurology, 6th ed, pp1049-57)Presenilin-2: Integral membrane protein of Golgi and endoplasmic reticulum. Its homodimer is an essential component of the gamma-secretase complex that catalyzes the cleavage of membrane proteins such as NOTCH RECEPTORS and AMYLOID BETA-PEPTIDES precursors. PSEN2 mutations cause ALZHEIMER DISEASE type 4.Peptidyl-Dipeptidase A: A peptidyl-dipeptidase that catalyzes the release of a C-terminal dipeptide, -Xaa-*-Xbb-Xcc, when neither Xaa nor Xbb is Pro. It is a Cl(-)-dependent, zinc glycoprotein that is generally membrane-bound and active at neutral pH. It may also have endopeptidase activity on some substrates. (From Enzyme Nomenclature, 1992) EC 3.4.15.1.Dipeptides: Peptides composed of two amino acid units.Leukemia, Promyelocytic, Acute: An acute myeloid leukemia in which abnormal PROMYELOCYTES predominate. It is frequently associated with DISSEMINATED INTRAVASCULAR COAGULATION.Gamma Rays: Penetrating, high-energy electromagnetic radiation emitted from atomic nuclei during NUCLEAR DECAY. The range of wavelengths of emitted radiation is between 0.1 - 100 pm which overlaps the shorter, more energetic hard X-RAYS wavelengths. The distinction between gamma rays and X-rays is based on their radiation source.Metalloendopeptidases: ENDOPEPTIDASES which use a metal such as ZINC in the catalytic mechanism.ADAM Proteins: A family of membrane-anchored glycoproteins that contain a disintegrin and metalloprotease domain. They are responsible for the proteolytic cleavage of many transmembrane proteins and the release of their extracellular domain.ThiophenesMolecular Sequence Data: 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.Solubility: The ability of a substance to be dissolved, i.e. to form a solution with another substance. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed)Membrane Proteins: 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.Amino Acid Sequence: 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.Phenylalanine: An essential aromatic amino acid that is a precursor of MELANIN; DOPAMINE; noradrenalin (NOREPINEPHRINE), and THYROXINE.Peptide Fragments: Partial proteins formed by partial hydrolysis of complete proteins or generated through PROTEIN ENGINEERING techniques.Protein Processing, Post-Translational: Any of various enzymatically catalyzed post-translational modifications of PEPTIDES or PROTEINS in the cell of origin. These modifications include carboxylation; HYDROXYLATION; ACETYLATION; PHOSPHORYLATION; METHYLATION; GLYCOSYLATION; ubiquitination; oxidation; proteolysis; and crosslinking and result in changes in molecular weight and electrophoretic motility.Cell Line: Established cell cultures that have the potential to propagate indefinitely.Hydroxamic Acids: A class of weak acids with the general formula R-CONHOH.Matrix Metalloproteinase Inhibitors: Compounds that inhibit the enzyme activity or activation of MATRIX METALLOPROTEINASES.Cells, Cultured: 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.Detergents: Purifying or cleansing agents, usually salts of long-chain aliphatic bases or acids, that exert cleansing (oil-dissolving) and antimicrobial effects through a surface action that depends on possessing both hydrophilic and hydrophobic properties.Affinity Labels: Analogs of those substrates or compounds which bind naturally at the active sites of proteins, enzymes, antibodies, steroids, or physiological receptors. These analogs form a stable covalent bond at the binding site, thereby acting as inhibitors of the proteins or steroids.Interferon-gamma: The major interferon produced by mitogenically or antigenically stimulated LYMPHOCYTES. It is structurally different from TYPE I INTERFERON and its major activity is immunoregulation. It has been implicated in the expression of CLASS II HISTOCOMPATIBILITY ANTIGENS in cells that do not normally produce them, leading to AUTOIMMUNE DISEASES.CHO Cells: CELL LINE derived from the ovary of the Chinese hamster, Cricetulus griseus (CRICETULUS). The species is a favorite for cytogenetic studies because of its small chromosome number. The cell line has provided model systems for the study of genetic alterations in cultured mammalian cells.Goldfish: Common name for Carassius auratus, a type of carp (CARPS).Cricetinae: A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS.Brain: The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM.Signal Transduction: 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.Cell Membrane: The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells.Zinc: A metallic element of atomic number 30 and atomic weight 65.38. It is a necessary trace element in the diet, forming an essential part of many enzymes, and playing an important role in protein synthesis and in cell division. Zinc deficiency is associated with ANEMIA, short stature, HYPOGONADISM, impaired WOUND HEALING, and geophagia. It is known by the symbol Zn.Transfection: 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.Swine: Any of various animals that constitute the family Suidae and comprise stout-bodied, short-legged omnivorous mammals with thick skin, usually covered with coarse bristles, a rather long mobile snout, and small tail. Included are the genera Babyrousa, Phacochoerus (wart hogs), and Sus, the latter containing the domestic pig (see SUS SCROFA).Patents as Topic: Exclusive legal rights or privileges applied to inventions, plants, etc.Presenilin-1: Integral membrane protein of Golgi and endoplasmic reticulum. Its homodimer is an essential component of the gamma-secretase complex that catalyzes the cleavage of membrane proteins such as NOTCH RECEPTORS and AMYLOID BETA-PEPTIDES precursors. PSEN1 mutations cause early-onset ALZHEIMER DISEASE type 3 that may occur as early as 30 years of age in humans.PubMed: A bibliographic database that includes MEDLINE as its primary subset. It is produced by the National Center for Biotechnology Information (NCBI), part of the NATIONAL LIBRARY OF MEDICINE. PubMed, which is searchable through NLM's Web site, also includes access to additional citations to selected life sciences journals not in MEDLINE, and links to other resources such as the full-text of articles at participating publishers' Web sites, NCBI's molecular biology databases, and PubMed Central.Cell Line, Tumor: A cell line derived from cultured tumor cells.Breast: In humans, one of the paired regions in the anterior portion of the THORAX. The breasts consist of the MAMMARY GLANDS, the SKIN, the MUSCLES, the ADIPOSE TISSUE, and the CONNECTIVE TISSUES.Breast Neoplasms: Tumors or cancer of the human BREAST.
The peptides derive from the amyloid precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield A ... Yin YI, Bassit B, Zhu L, Yang X, Wang C, Li YM (Aug 2007). "{gamma}-Secretase Substrate Concentration Modulates the Aβ42/Aβ40 ... Roberts SB (Dec 2002). "Gamma-secretase inhibitors and Alzheimer's disease". Advanced Drug Delivery Reviews. 54 (12): 1579-88. ... and γ-secretase are highly sought after. In order to initiate partial inhibition of β- and γ-secretase, a compound is needed ...
... also known as gamma-secretase activating protein (GSAP) is a protein that in humans is encoded by the ... St George-Hyslop P, Schmitt-Ulms G (September 2010). "Alzheimer's disease: Selectively tuning gamma-secretase". Nature. 467 ( ... "Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease". Nature. 467 (7311): 95-8. doi:10.1038/ ... works by directly inhibiting the γ-secretase. While semagacestat reduces β-amyloid plaque formation in AD patients, γ-secretase ...
... (presenilin enhancer 2) is a protein that is a regulatory component of the gamma secretase complex, a protease complex ... Kaether C, Haass C, Steiner H. (2006). Assembly, trafficking and function of gamma-secretase. Neurodegener Dis 3(4-5):275-83. ... The gamma secretase complex consists of PEN-2, APH-1, nicastrin, and the catalytic subunit presenilin. PEN-2 is a 101-amino ... gamma-secretase cleavage of betaAPP, and presenilin protein accumulation. Dev Cell 3(1):85-97. PMID 12110170 Hasegawa H, Sanjo ...
Presenilin-1 is one of the four core proteins in the gamma secretase complex, which is considered to play an important role in ... Based on evidence that a gamma-secretase inhibitor binds to the fragments, the cleaved presenilin complex is considered to be ... The same step can be also blocked by several gamma-secretase inhibitors, shown in the same study. These evidences collectively ... Spasic D, Annaert W (February 2008). "Building gamma-secretase: the bits and pieces". J. Cell Sci. 121 (Pt 4): 413-20. doi: ...
... (abbreviated NCT) is a protein that is part of the gamma secretase protein complex, which is one of the proteases ... Baulac S, LaVoie MJ, Kimberly WT, Strahle J, Wolfe MS, Selkoe DJ, Xia W (Nov 2003). "Functional gamma-secretase complex ... Kaether C, Haass C, Steiner H (2006). "Assembly, trafficking and function of gamma-secretase". Neuro-Degenerative Diseases. 3 ( ... and gamma-secretase substrates". Neurobiology of Disease. 14 (2): 194-204. doi:10.1016/S0969-9961(03)00123-2. PMID 14572442. Gu ...
... homologs in other organisms, including humans, have since been identified as components of the gamma secretase complex ... All of the components of the gamma-secretase complex undergo extensive post-translational modification, especially proteolytic ... Gamma-secretase cleavage of APP is one of two proteolytic steps required to generate the peptide known as amyloid beta, whose ... A conserved GXXXG motif in APH-1 is critical for assembly and activity of the gamma-secretase complex. J Biol Chem 279(6):4144- ...
An example of a decrease in expression of LRP8 is when gamma secretase cleaves LRP8 as well as the ligand amyloid precursor ... The amyloid-β peptide is derived from the cleavage of APP by gamma secretase. ApoER2 works to reduce APP trafficking by ... In addition, the expression of ApoER2 within intracellular compartments leads to increased gamma secretase activity, a protease ... "Differential glycosylation regulates processing of lipoprotein receptors by gamma-secretase". J. Biol. Chem. 278 (39): 37386-92 ...
... is the sub-component of gamma secretase that is responsible for the cutting of APP. Gamma secretase can cut APP at ... This can come about by various effects of the mutations upon gamma secretase. Presenilins are also implicated in the processing ... provides strong evidence of a nine transmembrane structure with cleavage and assembly into the gamma-secretase complex prior to ... To form Aβ, APP must be cut by two enzymes, beta secretases and gamma secretase. ...
In vitro studies identified that a modified version of imatinib can bind to gamma-secretase activating protein (GSAP). GSAP ... "Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease". Nature. 467 (7311): 95-8. doi:10.1038/ ...
Lee SF, Srinivasan B, Sephton CF, Dries DR, Wang B, Yu C, Wang Y, Dewey CM, Shah S, Jiang J, Yu G (Aug 2011). "Gamma-secretase- ...
2010). "Disposition and metabolism of semagacestat, a {gamma}-secretase inhibitor, in humans". Drug metabolism and disposition ... Semagacestat blocks the enzyme γ-secretase, which (along with β-secretase) is responsible for APP proteolysis. Phase III double ... γ-Secretase has other targets, for example the notch receptor. It is not known whether this could cause long-term side effects ... This contrasts with the results from the phase III trial of Myriad's γ-secretase modulator tarenflurbil, which found that the ...
Massey LK, Mah AL, Monteiro MJ (2006). "Ubiquilin regulates presenilin endoproteolysis and modulates gamma-secretase components ...
Cleavage by gamma secretase within the membrane-spanning domain after beta-secretase cleavage generates the amyloid-beta ... It is commonly cleaved by proteases in the secretase family; alpha secretase and beta secretase both remove nearly the entire ... whereas APP molecules outside a raft are differentially cleaved by the non-amyloidogenic alpha secretase. Gamma secretase ... "TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity". Nature. 440 (7088 ...
"A family of membrane proteins associated with presenilin expression and gamma-secretase function". FASEB J. 22 (3): 819-27. doi ...
... the active subunit of gamma secretase, which is an aspartyl protease Signal peptide peptidases (SPPs) and SPP-like proteases, ... "A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain". Nature. 398 (6727): 518 ... "Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity". Nature. 398 ...
Ikeuchi T, Sisodia SS (2003). "The Notch ligands, Delta1 and Jagged2, are substrates for presenilin-dependent "gamma-secretase ...
"A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain". Nature. 398 (6727): 518 ...
... (RG-4733) is a gamma secretase inhibitor being studied as an anti-cancer drug. Targeting gamma secretase inhibits ...
2006). "A gamma-secretase-like intramembrane cleavage of TNFalpha by the GxGD aspartyl protease SPPL2b". Nat. Cell Biol. 8 (8 ...
Gamma secretase is a protein complex thought to be a fundamental building block in the development of the amyloid beta peptide ... A gamma secretase inhibitor, semagacestat, failed to show any benefit to Alzheimer's disease patients in clinical trials. ... 2003). "NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo". J. Clin. Invest. 112 (3): ... Tarenflurbil (MPC-7869, formerly R-flubiprofen) is a gamma secretase modulator sometimes called a selective amyloid beta 42 ...
Other methods being studied include the use of antioxidants, gamma secretase inhibition, adrenergic agonists, and memantine. ...
Gao Y, Pimplikar SW (2002). "The gamma -secretase-cleaved C-terminal fragment of amyloid precursor protein mediates signaling ...
2006). "TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity". Nature. 440 ...
2003). "gamma-Secretase cleavage and binding to FE65 regulate the nuclear translocation of the intracellular C-terminal domain ... 2003). "Processing of beta-amyloid precursor-like protein-1 and -2 by gamma-secretase regulates transcription". J. Biol. Chem. ... gamma-, and epsilon-like cleavages: modulation of APLP-1 processing by n-glycosylation". J. Biol. Chem. 279 (18): 18146-56. doi ...
The protein is also a member of a heteromeric secretase complex and regulates the complex's gamma-secretase activity without ... 2006). "TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity". Nature. 440 ... affecting its epsilon-secretase activity. Mutations in this gene have been associated with early-onset familial Alzheimer's ...
Gamma secretase. Pages I've recently made significant changes to. *Quadriceps muscle. *Bob Woolmer ...
Recent research has shown that interaction of the gamma secretase complex with the γ-secretase activating protein facilitates ... "TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity". Nature. 440 (7088 ... The gamma secretase complex is unusual among proteases in having a "sloppy" cleavage site at the C-terminal site in amyloid ... Gamma secretase is also critical in the related processing of several other type I integral membrane proteins, such as Notch, ...
The compounds inhibit gamma secretase without affecting Notch signalling, and hence find use in the treatment or prevention of ... wherein X is CH2, O or S. The compounds inhibit gamma secretase without affecting Notch signalling, and hence find use in the ... The compounds inhibit gamma secretase without affecting Notch signalling, and hence find use in the treatment or prevention of ... A minor portion of APPs is released by a β-secretase, which cleaves near the NH2-terminus of Aβ and produces COOH-terminal ...
inhibit the processing of APP by gamma-secretase, and hence are useful in treating or preventing Alzheimers disease. ... In particular, the invention relates to novel cyclohexyl sulphones which inhibit the processing of APP by γ-secretase, and ... 0058] The compounds of formula I have an activity as modulators of the processing of APP by γ-secretase. ... 0004] There are relatively few reports in the literature of compounds with inhibitory activity towards γ-secretase, as measured ...
Cryoelectron microscopy structure of purified gamma-secretase at 12 A resolution.. Osenkowski P1, Li H, Ye W, Li D, Aeschbach L ... Gamma-secretase, an integral membrane protein complex, catalyzes the intramembrane cleavage of the beta-amyloid precursor ... Here, we report that purified active human gamma-secretase in digitonin has a total molecular mass of approximately 230 kDa ... We further report the three-dimensional structure of the gamma-secretase complex at 12 A resolution as obtained by cryoelectron ...
So gamma secretase modulators could still be worth while? Instead of inhibiting the activity of gamma secretase, these modulate ... A GPCR/secretase complex regulates beta- and gamma-secretase specificity for Abeta production and contributes to AD ... Presenilin have been tabbed as the catalytic subunit of the gamma secretase assuming that they were part of gamma secretases ... Should we be thinking about beta-secretase differently in view of the (gamma secretase) hypothesis? Sorry, not an AD expert ...
... program combining gamma secretase inhibitors and tumor necrosis factor (TNF) receptor superfamily member 17 (BCMA; TNFRSF17; ... program combining gamma secretase inhibitors and tumor necrosis factor (TNF) receptor superfamily member 17 (BCMA; TNFRSF17; ...
We now showed that repression of PS1 transcription by JNK inhibitor SP600125 inhibited gamma-secretase med … ... Transcriptional regulation of the presenilin-1 gene controls gamma-secretase activity Front Biosci (Elite Ed). 2010 Jan 1;2:22- ... We now showed that repression of PS1 transcription by JNK inhibitor SP600125 inhibited gamma-secretase mediated processing of ...
A gamma-secretase-like intramembrane cleavage of TNFalpha by the GxGD aspartyl protease SPPL2b.. Fluhrer R1, Grammer G, Israel ... Gamma-secretase and signal peptide peptidase (SPP) are unusual GxGD aspartyl proteases, which mediate intramembrane proteolysis ...
The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its ... PSENEN modulates both endoproteolysis of presenilin and gamma-secretase activity (PubMed:12522139, PubMed:12763021, PubMed: ... Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral ... "Gamma-secretase gene mutations in familial acne inversa.". Wang B., Yang W., Wen W., Sun J., Su B., Liu B., Ma D., Lv D., Wen Y ...
... Nature. 1999 Apr 8;398( ... Moreover, several gamma-secretase inhibitors block this same step in Notch processing, indicating that related protease ... Thus the targeting of gamma-secretase for the treatment of Alzheimers disease may risk toxicity caused by reduced Notch ... A deficiency in presenilin-1 (PS1) inhibits processing of APP by gamma-secretase in mammalian cells, and genetic interactions ...
View and select products within our Gamma-secretase Inhibitors category available for immediate purchase. ... gamma-Secretase Inhibitor I γ-Secretase Inhibitor I is a γ-secretase inhibitor 133407-83-7 sc-301796 sc-301796A 5 mg. 1 mg. $ ... gamma-Secretase Inhibitor XI γ-Secretase Inhibitor XI is a γ-secretase inhibitor useful in amyloid-β studies sc-222305 5 mg. $ ... gamma-Secretase Inhibitor III γ-Secretase Inhibitor III is a cell-permeable, reversible inhibitor of γ-secretase sc-302013 sc- ...
Related Gamma-secretase Products0. * Nirogacestat (PF-03084014, PF-3084014) New Nirogacestat (PF-03084014, PF-3084014) is a ... Semagacestat (LY450139) is a γ-secretase blocker for Aβ42, Aβ40 and Aβ38 with IC50 of 10.9 nM, 12.1 nM and 12.0 nM, also ... Dibenzazepine (YO-01027) is a dipeptidic γ-secretase inhibitor with IC50 of 2.6 nM and 2.9 nM in cell-free assays for APPL and ... Avagacestat (BMS-708163) is a potent, selective, orally bioavailable γ-secretase inhibitor of Aβ40 and Aβ42 with IC50 of 0.3 nM ...
... active subunit of gamma-secretase) endoproteolysis and hypoxia. In this review we discuss how gamma-secretase is regulated with ... including but not limited to the essential gamma-secretase subunits, nonessential (modulatory) subunits, and gamma-secretase ... gamma-Secretase also cleaves Notch, among many other type I transmembrane substrates. Despite its seemingly promiscuous ... gamma-secretase activity is tightly regulated. This regulation is a function of many cellular entities, ...
... gamma secretase subunit ELISA Kits from LifeSpan BioSciences from leading suppliers on Biocompare. View specifications, prices ... aph1 homolog A, gamma secretase subunit ELISA Kits from LifeSpan BioSciences. Clear ... aph1 homolog A, gamma secretase subunit ELISA Kits from LifeSpan BioSciences. The ELISA (enzyme-linked immunosorbent assay) is ... Your search returned 2 aph1 homolog A, gamma secretase subunit ELISA ELISA Kit across 1 supplier. ...
Experimental: Group B (gamma-secretase inhibitor RO4929097, surgery) Patients receive gamma-secretase/Notch signalling pathway ... Experimental: Group A (gamma-secretase inhibitor RO4929097) Patients receive gamma-secretase/Notch signalling pathway inhibitor ... patients receive gamma-secretase inhibitor RO4929097 as in group A.. Interventions: *Drug: gamma-secretase/Notch signalling ... Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Recurrent or Progressive Glioblastoma. ...
... by a highly specific inhibitor of gamma-secretase and was absent in mouse embryonic fibroblasts deficient in gamma-secretase ... Regulated intramembrane proteolysis of the interleukin-1 receptor II by alpha-, beta-, and gamma-secretase.. [Peer-Hendrik Kuhn ... Ectodomain shedding and intramembrane proteolysis of the amyloid precursor protein (APP) by alpha-, beta- and gamma-secretase ... This fragment undergoes further intramembrane proteolysis by gamma-secretase, leading to the generation of the soluble ...
Experimental: Arm I (gamma-secretase inhibitor RO4929097) Patients receive gamma-secretase/Notch signalling pathway inhibitor ... Experimental: Arm II (vismodegib and gamma-secretase inhibitor RO4929097) Patients receive vismodegib PO and gamma-secretase/ ... Drug: Gamma-Secretase Inhibitor RO4929097 Other: Laboratory Biomarker Analysis Other: Pharmacological Study Drug: Vismodegib ... Gamma-secretase/notch signalling pathway inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes ...
Gamma Secretase Inhibition by BMS-906024 Enhances Efficacy of Paclitaxel in Lung Adenocarcinoma. Katherine M. Morgan, Bruce S. ... Gamma-secretase inhibitor prevents Notch3 activation and reduces proliferation in human lung cancers. Cancer Res 2007;67:8051-7 ... gamma-Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct. EMBO Mol Med 2017;9:950- ... Gamma secretase inhibitors (GSI) are a class of small-molecule Notch inhibitors that have been used recently in cancer clinical ...
Because the list of gamma-secretase substrates is growing quickly and this enzyme is a cancer and Alzheimers disease ... Intriguingly, the transcription of TERA, a gene of unknown function, is affected by gamma-secretase activity and was ... Single genes with the most pronounced transcriptional susceptibility to gamma-secretase activity were evaluated by real-time ... CONCLUSIONS/SIGNIFICANCE: Investigating the effects of gamma-secretase activity on gene transcription has revealed several ...
Thus, the gamma-secretase inhibitor GSI1 has a complex mode of action to inhibit breast cancer cell survival and may represent ... Gamma-secretase activity is vital for the transmembrane cleavage of Notch receptors and the subsequent migration of their ... Inhibition of gamma-secretase induces G2/M arrest and triggers apoptosis in breast cancer cells. ... We tested the effect of three different gamma-secretase inhibitors (GSIs) in breast cancer cells. One inhibitor (GSI1) was ...
Gamma-Secretase,Modulator,biological,advanced biology technology,biology laboratory technology,biology device technology,latest ... As EVP-0962 does not affect other gamma secretase substrates required for normal function, such as Notch, it is predicted to ... EVP-0962 is a proprietary small molecule that belongs to a new generation of potential Alzheimer drugs known as gamma-secretase ... As a gamma-secretase modulator, EVP-0962 selectively inhibits the production of the toxic AB42 peptide without affecting the ...
Results]The effect of the sustained local delivery of MDL28170, a gamma-secretase inhibitor, on hearing and hair cell induction ... Therapeutic potential of a gamma-secretase inhibitor for hearing restoration in a guinea pig model with noise-induced hearing ... Conclusion]These findings strongly suggest that local sustained delivery of a gamma-secretase inhibitor into the cochlea could ... present study aimed to illustrate the feasibility of pharmacologically inhibiting Notch signaling by using a gamma-secretase ...
The gamma-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a ... gamma-Secretase inhibition represents a major therapeutic strategy for lowering amyloid beta (A beta) peptide production in ... Alzheimers Disease: Presenilin 2-Sparing gamma-Secretase Inhibition Is a Tolerable A beta Peptide-Lowering Strategy. Borgegard ... Progress toward clinical use of gamma-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, ...
1-Methoxyphaseollidin: Novel gamma secretase inhibitor targeting notch-1 signaling in breast cancer stem cells [abstract]. In: ... Abstract 2903: 1-Methoxyphaseollidin: Novel gamma secretase inhibitor targeting notch-1 signaling in breast cancer stem cells. ... Abstract 2903: 1-Methoxyphaseollidin: Novel gamma secretase inhibitor targeting notch-1 signaling in breast cancer stem cells ... Abstract 2903: 1-Methoxyphaseollidin: Novel gamma secretase inhibitor targeting notch-1 signaling in breast cancer stem cells ...
... secretase, which includes the following steps: (i) contacting a first biological composition containing .gamma.-secretase or a ... gamma.-secretase; and (iv) identifying the candidate compounds selected in step (iii) as compounds which affect the processing ... Further, the .gamma.-secretase of the present invention may be a mutant.gamma.-secretase. The mutant .gamma.-secretase is a ... gamma.-secretase or EphA4, an analogue of .gamma.-secretase or EphA4, or a mutant of .gamma.-secretase or EphA4.. When a first ...
  • EVP-0962 is a proprietary small molecule that belongs to a new generation of potential Alzheimer drugs known as gamma-secretase modulators (GSMs). (bio-medicine.org)
  • The loose state should be selectively disfavored by -secretase modulators to increase C99 trimming and reduce the formation of longer Aβ, a strategy that is currently much explored but has lacked a structural basis. (medworm.com)
  • Significance: The dynamic characterization of APP is expected to rationalize the design of -secretase modulators. (epfl.ch)
  • Using medicinal chemistry, this research will optimize a series of novel gamma-secretase modulators with the hope of developing a preventive treatment for traumatic brain injury-induced neurodegeneration. (curealz.org)
  • The two next-generation classes of compound that are currently in clinical trials target an enzyme that cuts APP, known as gamma secretase. (alzheimersweekly.com)
  • Mutations in the γ-secretase genes NCSTN, PSENEN, and PSEN1 underlie rare forms of hidradenitis suppurativa (acne inversa). (medlineplus.gov)
  • γ-Secretase mutations in hidradenitis suppurativa: new insights into disease pathogenesis. (medlineplus.gov)
  • COMMENT More analyses on mutations near alpha-site are welcome because they should contribute to the whole pathological understanding of Abeta metabolism together with beta- and gamma-site cleavages. (alzforum.org)
  • gamma secretase can cleave APP in any of multiple sites to generate a peptide of variable length, most typically from 39 to 42 amino acids long, with Aβ40 the most common isoform and Aβ42 the most susceptible to conformational changes leading to amyloid fibrillogenesis. (wikipedia.org)
  • To get near gamma secretase, another enzyme must first cleave APP in another place so one extramembrane fragment is short. (wordpress.com)
  • In 2014, a three-dimensional structure of an intact human gamma-secretase complex was determined by cryo-electron microscopy single-particle analysis at 4.5 angstrom resolution and in 2015 an atomic-resolution (3.4 angstrom) cryo-EM structure was reported. (wikipedia.org)
  • Here, we report that purified active human gamma-secretase in digitonin has a total molecular mass of approximately 230 kDa when measured by scanning transmission electron microscopy. (nih.gov)
  • The association of the sporadic AD phenotype with a distinct p3-Alc:Ap covariant ratio signature provides evidence that y-secretase dysfunction may contribute to the pathogenesis of sporadic AD. (grantome.com)
  • I. To determine the maximum-tolerated dose (MTD) of gamma-secretase inhibitor RO4929097 (RO4929097) when given in combination with fixed-dose Hedgehog antagonist GDC-0449 (GDC-0449) which will become the recommended dose for the phase II portion of this study. (clinicaltrials.gov)
  • demonstrated that the activity of the gamma-secretase complex was required for the release of Notch2 intracellular domain, NICD2, and the ensuing NICD2-mediated transcriptional response (Saxena et al. (reactome.org)
  • Taken together, our study demonstrates a critical role of Nct in the stability and proper intracellular trafficking of other components of the PS1/ gamma-secretase complex but not in maintaining the association of PEN-2, APH-1, and full-length PS1. (xmu.edu.cn)