Target Information
| Target General Information | Top | |||||
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| Target ID |
T99840
(Former ID: TTDC00051)
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| Target Name |
Gamma-secretase (GS)
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| Synonyms |
Presenilin-stabilization factor-like; PSFL; Aph-1beta
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| Gene Name |
APH1A; APH1B; NCSTN; PSENEN; PSEN1
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Desmoid tumour [ICD-11: 2F7C] | |||||
| 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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| UniProt ID | ||||||
| Sequence |
MGAAVFFGCTFVAFGPAFALFLITVAGDPLRVIILVAGAFFWLVSLLLASVVWFILVHVT
DRSDARLQYGLLIFGAAVSVLLQEVFRFAYYKLLKKADEGLASLSEDGRSPISIRQMAYV SGLSFGIISGVFSVINILADALGPGVVGIHGDSPYYFLTSAFLTAAIILLHTFWGVVFFD ACERRRYWALGLVVGSHLLTSGLTFLNPWYEASLLPIYAVTVSMGLWAFITAGGSLRSIQ RSLLCRRQEDSRVMVYSALRIPPED Click to Show/Hide
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| Drugs and Modes of Action | Top | |||||
|---|---|---|---|---|---|---|
| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Nirogacestat | Drug Info | Approved | Desmoid tumour | [1] | |
| Clinical Trial Drug(s) | [+] 16 Clinical Trial Drugs | + | ||||
| 1 | (S)-FLURBIPROFEN | Drug Info | Preregistration | Myalgia | [2] | |
| 2 | AMG 386 | Drug Info | Phase 3 | Neuropathic pain | [3] | |
| 3 | Semagacestat | Drug Info | Phase 3 | Parkinson disease | [4], [5] | |
| 4 | AL102 | Drug Info | Phase 2 | Desmoid tumour | [6] | |
| 5 | BMS-708163 | Drug Info | Phase 2 | Alzheimer disease | [7], [8] | |
| 6 | CHF-5074 | Drug Info | Phase 2 | Alzheimer disease | [9], [10] | |
| 7 | MK-0752 | Drug Info | Phase 2 | Alzheimer disease | [11] | |
| 8 | RO-4929097 | Drug Info | Phase 2 | Breast cancer | [12], [13] | |
| 9 | Begacestat | Drug Info | Phase 1 | Alzheimer disease | [14], [15] | |
| 10 | E-2212 | Drug Info | Phase 1 | Alzheimer disease | [16] | |
| 11 | E2012 | Drug Info | Phase 1 | Alzheimer disease | [17], [18] | |
| 12 | GSI-136 | Drug Info | Phase 1 | Alzheimer disease | [19] | |
| 13 | NGP 555 | Drug Info | Phase 1 | Alzheimer disease | [20], [21] | |
| 14 | PF-06648671 | Drug Info | Phase 1 | Alzheimer disease | [20] | |
| 15 | PF-06648671 | Drug Info | Phase 1 | Alzheimer disease | [22] | |
| 16 | SPI-014 | Drug Info | Phase 1 | Hypophosphatasia | [23] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 14 Modulator drugs | + | ||||
| 1 | Nirogacestat | Drug Info | [1] | |||
| 2 | Semagacestat | Drug Info | [26] | |||
| 3 | BMS-708163 | Drug Info | [28] | |||
| 4 | CHF-5074 | Drug Info | [29] | |||
| 5 | MK-0752 | Drug Info | [11] | |||
| 6 | RO-4929097 | Drug Info | [13], [30] | |||
| 7 | Begacestat | Drug Info | [15] | |||
| 8 | E-2212 | Drug Info | [31] | |||
| 9 | E2012 | Drug Info | [32], [33] | |||
| 10 | GSI-136 | Drug Info | [34] | |||
| 11 | NGP 555 | Drug Info | [20] | |||
| 12 | PF-06648671 | Drug Info | [20] | |||
| 13 | PF-06648671 | Drug Info | [35] | |||
| 14 | SPI-014 | Drug Info | [36] | |||
| Inhibitor | [+] 12 Inhibitor drugs | + | ||||
| 1 | (S)-FLURBIPROFEN | Drug Info | [24] | |||
| 2 | AMG 386 | Drug Info | [25] | |||
| 3 | AL102 | Drug Info | [27] | |||
| 4 | R-flurbiprofen | Drug Info | [24] | |||
| 5 | (2S,3R)-2-(benzyloxy)-3-methoxycyclohexanone | Drug Info | [37] | |||
| 6 | (5R,6S)-5,6-bis(benzyloxy)cyclohex-2-enone | Drug Info | [37] | |||
| 7 | (5R,6S)-6-(benzyloxy)-5-methoxycyclohex-2-enone | Drug Info | [37] | |||
| 8 | 1-benzoyl-2-benzyl-1,2-dihydropyridin-3(6H)-one | Drug Info | [37] | |||
| 9 | Drug 311383 | Drug Info | [38] | |||
| 10 | Drug 311440 | Drug Info | [38] | |||
| 11 | Drug 311951 | Drug Info | [38] | |||
| 12 | Drug 311952 | Drug Info | [38] | |||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Cholesterol | Ligand Info | |||||
| Structure Description | Recognition of the Amyloid Precursor Protein by Human gamma-secretase | PDB:6IYC | ||||
| Method | Electron microscopy | Resolution | 2.60 Å | Mutation | Yes | [39] |
| PDB Sequence |
GAAVFFGCTF
11 VAFGPAFALF21 LITVAGDPLR31 VIILVAGAFF41 WLVSLLLASV51 VWFILVHVTD 61 RSDARLQYGL71 LIFGAAVSVL81 LQEVFRFAYY91 KLLKKADEGL101 ASLSEDGRSP 111 ISIRQMAYVS121 GLSFGIISGV131 FSVINILADA141 LGPGVVGIHG151 DSPYYFLTSA 161 FLTAAIILLH171 TFWGVVFFDA181 CERRRYWALG191 LVVGSHLLTS201 GLTFLNPWYE 211 ASLLPIYAVT221 VSMGLWAFIT231 AGGSLRSIQR241 SLL
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ARG66
3.518
TYR69
3.350
ILE73
4.010
SER153
4.583
TYR155
3.554
THR159
4.240
PHE162
3.867
ARG186
4.260
TRP188
3.996
LEU192
3.698
LEU199
4.360
GLY202
3.240
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | FDA Approved Drug Products from FDA Official Website. 2023. Application Number: 217677 | |||||
| REF 2 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025057) | |||||
| REF 3 | Emerging drugs in neuropathic pain. Expert Opin Emerg Drugs. 2007 Mar;12(1):113-26. | |||||
| REF 4 | URL: 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 5 | ClinicalTrials.gov (NCT01035138) A Study of Semagacestat for Alzheimer's Patients. U.S. National Institutes of Health. | |||||
| REF 6 | ClinicalTrials.gov (NCT04871282) A Study of AL102 in Patients With Progressing Desmoid Tumors (RINGSIDE). U.S. National Institutes of Health. | |||||
| REF 7 | URL: 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 8 | 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 9 | URL: 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 10 | 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 11 | 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 12 | URL: 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 13 | 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 14 | URL: 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 15 | 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 16 | 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 17 | URL: 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 18 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026719) | |||||
| REF 19 | ClinicalTrials.gov (NCT00719394) Study Evaluating Safety of GSI 136 in Young and Elderly Japanese Males. U.S. National Institutes of Health. | |||||
| REF 20 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 21 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 22 | ClinicalTrials.gov (NCT02407353) A Study to Evaluate the Pharmacodynamic Effects of Single Oral Doses of PF-06648671 on beta-Amyloid (Abeta) Concentrations in Cerebrospinal Fluid (CSF). U.S. National Institutes of Health. | |||||
| REF 23 | ClinicalTrials.gov (NCT01560884) Study to Assess the Safety and the Phosphate Binding Capacity of Renazorb. U.S. National Institutes of Health. | |||||
| REF 24 | The geminal dimethyl analogue of Flurbiprofen as a novel Abeta42 inhibitor and potential Alzheimer's disease modifying agent. Bioorg Med Chem Lett. 2006 Apr 15;16(8):2219-23. | |||||
| REF 25 | Clinical pipeline report, company report or official report of Roche (2009). | |||||
| REF 26 | A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med. 2013 Jul 25;369(4):341-50. | |||||
| REF 27 | Clinical pipeline report, company report or official report of Ayala Pharmaceuticals. | |||||
| REF 28 | 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 29 | CHF5074, a novel gamma-secretase modulator, attenuates brain beta-amyloid pathology and learning deficit in a mouse model of Alzheimer's disease.Br J Pharmacol.2009 Mar;156(6):982-93. | |||||
| REF 30 | Phase 2 study of RO4929097, a gamma-secretase inhibitor, in metastatic melanoma: SWOG 0933.Cancer.2015 Feb 1;121(3):432-440. | |||||
| REF 31 | Development and mechanism of gamma-secretase modulators for Alzheimer's disease. Biochemistry. 2013 May 14;52(19):3197-216. | |||||
| REF 32 | Chemical Biology, Molecular Mechanism and Clinical Perspective of -Secretase Modulators in Alzheimer's Disease.Curr Neuropharmacol.2011 Dec;9(4):598-622. | |||||
| REF 33 | Lactams as beta secretase inhibitors | |||||
| REF 34 | Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41. | |||||
| REF 35 | Pharmacokinetic and Pharmacodynamic Effects of a -Secretase Modulator, PF-06648671, on CSF Amyloid- Peptides in Randomized Phase I Studies. Clin Pharmacol Ther. 2020 Jan;107(1):211-220. | |||||
| REF 36 | Modulation of gamma-secretase for the treatment of Alzheimer's disease. Int J Alzheimers Dis. 2012;2012:210756. | |||||
| REF 37 | Novel gamma-secretase inhibitors discovered by library screening of in-house synthetic natural product intermediates. Bioorg Med Chem Lett. 2006 Jul 15;16(14):3813-6. | |||||
| REF 38 | Discovery of a Subnanomolar helical D-tridecapeptide inhibitor of gamma-secretase. J Med Chem. 2004 Jul 29;47(16):3931-3. | |||||
| REF 39 | Recognition of the amyloid precursor protein by human Gamma-secretase. Science. 2019 Feb 15;363(6428):eaaw0930. | |||||
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