Target Information

Target General Infomation
Target ID
T99840
Former ID
TTDC00051
Target Name
Gamma-secretase
Synonyms
APH; Aph-1beta; PSFL; Presenilin-stabilization factor-like
Target Type
Clinical Trial
Disease Alzheimer disease [ICD9: 331; ICD10: G30]
Alzheimer disease; Cancer [ICD9:331, 140-229; ICD10: G30, C00-C96]
Breast cancer [ICD9: 174, 175; ICD10: C50]
Parkinson's disease [ICD9: 332; ICD10: G20]
Function
Probable subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral proteins such as Notch receptors and APP (beta-amyloid precursor protein). It probably represents a stabilizing cofactor for the presenilin homodimer that promotes the formation of a stable complex. Probably present in a minority of gamma-secretase complexes compared to APH1A.
BioChemical Class
APH-1 family
Target Validation
T99840
UniProt ID
Q96BI3||Q8WW43||Q9NZ42||Q92542||P49768
Drugs and Mode of Action
Drug(s) Semagacestat Drug Info Phase 3 Parkinson's disease [522898], [542008]
BMS-708163 Drug Info Phase 2 Alzheimer disease [522650], [541623]
CHF-5074 Drug Info Phase 2 Alzheimer disease [523375], [542362]
MK-0752 Drug Info Phase 2 Alzheimer disease [531099]
PF-03084014 Drug Info Phase 2 Alzheimer disease; Cancer [525008], [542711]
R-flurbiprofen Drug Info Phase 2 Discovery agent [521532], [542364]
RO-4929097 Drug Info Phase 2 Breast cancer [531882], [542361]
Begacestat Drug Info Phase 1 Alzheimer disease [530308], [542009]
E-2212 Drug Info Phase 1 Alzheimer disease [523211]
E2012 Drug Info Phase 1 Alzheimer disease [542379], [548575]
GSI-136 Drug Info Phase 1 Alzheimer disease [522382]
SPI-014 Drug Info Phase 1 Alzheimer disease [523843]
Inhibitor (2S,3R)-2-(benzyloxy)-3-methoxycyclohexanone Drug Info [528191]
(5R,6S)-5,6-bis(benzyloxy)cyclohex-2-enone Drug Info [528191]
(5R,6S)-6-(benzyloxy)-5-methoxycyclohex-2-enone Drug Info [528191]
(S)-FLURBIPROFEN Drug Info [528008]
1-benzoyl-2-benzyl-1,2-dihydropyridin-3(6H)-one Drug Info [528191]
Drug 311383 Drug Info [527143]
Drug 311440 Drug Info [527143]
Drug 311951 Drug Info [527143]
Drug 311952 Drug Info [527143]
R-flurbiprofen Drug Info [528008]
Modulator Begacestat Drug Info [530308]
BMS-708163 Drug Info [532002]
CHF-5074 Drug Info
E-2212 Drug Info [532323]
E2012 Drug Info
GSI-136 Drug Info [1572591]
MK-0752 Drug Info [531099]
PF-03084014 Drug Info
RO-4929097 Drug Info [531882]
Semagacestat Drug Info [532438]
SPI-014 Drug Info [532197]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Notch signaling pathway
Alzheimer&#039
s disease
PANTHER Pathway Alzheimer disease-amyloid secretase pathway
Alzheimer disease-presenilin pathway
Notch signaling pathway
Pathway Interaction Database Notch signaling pathway
Presenilin action in Notch and Wnt signaling
p75(NTR)-mediated signaling
Syndecan-3-mediated signaling events
Reactome Nuclear signaling by ERBB4
Regulated proteolysis of p75NTR
NRIF signals cell death from the nucleus
Activated NOTCH1 Transmits Signal to the Nucleus
Constitutive Signaling by NOTCH1 PEST Domain Mutants
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
NOTCH2 Activation and Transmission of Signal to the Nucleus
EPH-ephrin mediated repulsion of cells
WikiPathways Notch Signaling Pathway
Signaling by ERBB4
Signaling by NOTCH3
Signaling by NOTCH4
Signaling by NOTCH1
Signaling by NOTCH2
Notch Signaling Pathway
Signalling by NGF
References
Ref 521532ClinicalTrials.gov (NCT00045123) R-Flurbiprofen in Treating Patients With Localized Prostate Cancer at Risk of Recurrence. U.S. National Institutes of Health.
Ref 522382ClinicalTrials.gov (NCT00719394) Study Evaluating Safety of GSI 136 in Young and Elderly Japanese Males. U.S. National Institutes of Health.
Ref 522650ClinicalTrials.gov (NCT00890890) A Multicenter, Double Blind, Placebo-Controlled, Safety and Tolerability Study of BMS-708163 in Patients With Prodromal Alzheimer's Disease. U.S. National Institutes of Health.
Ref 522898ClinicalTrials.gov (NCT01035138) A Study of Semagacestat for Alzheimer's Patients. U.S. National Institutes of Health.
Ref 523211ClinicalTrials.gov (NCT01221259) A Randomized, Double-blind, Placebo-controlled, Sequential Ascending, Single-dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of E2212 in Healthy Subjects. U.S. National Institutes of Health.
Ref 523375ClinicalTrials.gov (NCT01303744) Evaluation of Safety & Tolerability of Multiple Dose Regimens of CHF 5074 and Exploration of Effects on Potential Markers of Clinical Efficacy in Patients With Mild Cognitive Impairment. U.S. National Institutes of Health.
Ref 523843ClinicalTrials.gov (NCT01560884) Study to Assess the Safety and the Phosphate Binding Capacity of Renazorb. U.S. National Institutes of Health.
Ref 525008ClinicalTrials.gov (NCT02299635) A Study Evaluating PF-03084014 In Patients With Advanced Breast Cancer With Or Without Notch Alterations. U.S. National Institutes of Health.
Ref 530308Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer's disease. J Pharmacol Exp Ther. 2009 Nov;331(2):598-608.
Ref 531099Determination of the gamma-secretase inhibitor MK-0752 in human plasma by online extraction and electrospray tandem mass spectrometry (HTLC-ESI-MS/MS). J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Sep 1;878(25):2348-52.
Ref 531882Phase I study of RO4929097, a gamma secretase inhibitor of Notch signaling, in patients with refractory metastatic or locally advanced solid tumors. J Clin Oncol. 2012 Jul 1;30(19):2348-53.
Ref 541623(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6489).
Ref 542008(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6978).
Ref 542009(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6979).
Ref 542361(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7338).
Ref 542362(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7339).
Ref 542364(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7340).
Ref 542379(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7358).
Ref 542711(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7746).
Ref 548575Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026719)
Ref
Ref 527143J Med Chem. 2004 Jul 29;47(16):3931-3.Discovery of a Subnanomolar helical D-tridecapeptide inhibitor of gamma-secretase.
Ref 528008Bioorg Med Chem Lett. 2006 Apr 15;16(8):2219-23. Epub 2006 Feb 7.The geminal dimethyl analogue of Flurbiprofen as a novel Abeta42 inhibitor and potential Alzheimer's disease modifying agent.
Ref 528191Bioorg Med Chem Lett. 2006 Jul 15;16(14):3813-6. Epub 2006 May 8.Novel gamma-secretase inhibitors discovered by library screening of in-house synthetic natural product intermediates.
Ref 530308Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer's disease. J Pharmacol Exp Ther. 2009 Nov;331(2):598-608.
Ref 531099Determination of the gamma-secretase inhibitor MK-0752 in human plasma by online extraction and electrospray tandem mass spectrometry (HTLC-ESI-MS/MS). J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Sep 1;878(25):2348-52.
Ref 531882Phase I study of RO4929097, a gamma secretase inhibitor of Notch signaling, in patients with refractory metastatic or locally advanced solid tumors. J Clin Oncol. 2012 Jul 1;30(19):2348-53.
Ref 532002Safety and tolerability of the gamma-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol. 2012 Nov;69(11):1430-40.
Ref 532197Modulation of gamma-secretase for the treatment of Alzheimer's disease. Int J Alzheimers Dis. 2012;2012:210756.
Ref 532323Development and mechanism of gamma-secretase modulators for Alzheimer's disease. Biochemistry. 2013 May 14;52(19):3197-216.
Ref 532438A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med. 2013 Jul 25;369(4):341-50.
Ref 1572591Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

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