Target Information
Target General Infomation | |||||
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Target ID |
T99840
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Former ID |
TTDC00051
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Target Name |
Gamma-secretase
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Synonyms |
APH; Aph-1beta; PSFL; Presenilin-stabilization factor-like
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Target Type |
Clinical Trial
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Disease | Alzheimer disease; Cancer [ICD9:331, 140-229; ICD10: G30, C00-C96] | ||||
Alzheimer disease [ICD9: 331; ICD10: G30] | |||||
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.
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BioChemical Class |
APH-1 family
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Target Validation |
T99840
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UniProt ID | |||||
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' | |||||
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 521532 | ClinicalTrials.gov (NCT00045123) R-Flurbiprofen in Treating Patients With Localized Prostate Cancer at Risk of Recurrence. U.S. National Institutes of Health. | ||||
Ref 522382 | ClinicalTrials.gov (NCT00719394) Study Evaluating Safety of GSI 136 in Young and Elderly Japanese Males. U.S. National Institutes of Health. | ||||
Ref 522650 | ClinicalTrials.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 522898 | ClinicalTrials.gov (NCT01035138) A Study of Semagacestat for Alzheimer's Patients. U.S. National Institutes of Health. | ||||
Ref 523211 | ClinicalTrials.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 523375 | ClinicalTrials.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 523843 | ClinicalTrials.gov (NCT01560884) Study to Assess the Safety and the Phosphate Binding Capacity of Renazorb. U.S. National Institutes of Health. | ||||
Ref 525008 | ClinicalTrials.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 530308 | Begacestat (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 531099 | Determination 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 531882 | Phase 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 527143 | J Med Chem. 2004 Jul 29;47(16):3931-3.Discovery of a Subnanomolar helical D-tridecapeptide inhibitor of gamma-secretase. | ||||
Ref 528008 | Bioorg 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 528191 | Bioorg 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 530308 | Begacestat (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 531099 | Determination 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 531882 | Phase 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 532002 | Safety 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 532197 | Modulation of gamma-secretase for the treatment of Alzheimer's disease. Int J Alzheimers Dis. 2012;2012:210756. | ||||
Ref 532323 | Development and mechanism of gamma-secretase modulators for Alzheimer's disease. Biochemistry. 2013 May 14;52(19):3197-216. |
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