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Literature DB >> 22931393

BMS-708,163 targets presenilin and lacks notch-sparing activity.

Christina J Crump¹, Suita V Castro, Feng Wang, Nikolay Pozdnyakov, T Eric Ballard, Sangram S Sisodia, Kelly R Bales, Douglas S Johnson, Yue-Ming Li.

Abstract

The "Notch-sparing" γ-secretase inhibitor (GSI) BMS-708,163 (Avagacestat) is currently in phase II clinical trials for Alzheimer's disease. Unlike previously failed GSIs, BMS-708,163 is considered to be a promising drug candidate because of its reported Notch-sparing activity for the inhibition of Aβ production over Notch cleavage. We now report that BMS-708,163 binds directly to the presenilin-1 N-terminal fragment and that binding can be challenged by other pan-GSIs, but not by γ-secretase modulators. Furthermore, BMS-708,163 blocks the binding of four different active site-directed GSI photoaffinity probes. We therefore report that this compound acts as a nonselective γ-secretase inhibitor.

Entities: CellLine Chemical Disease Gene Species

Mesh：

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Year: 2012 PMID： 22931393 PMCID： PMC3470910 DOI： 10.1021/bi301137h

Source DB: PubMed Journal: Biochemistry ISSN： 0006-2960 Impact factor: 3.162

18 in total

1. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease.

Authors: Vladimir Coric; Christopher H van Dyck; Stephen Salloway; Niels Andreasen; Mark Brody; Ralph W Richter; Hilkka Soininen; Stephen Thein; Thomas Shiovitz; Gary Pilcher; Susan Colby; Linda Rollin; Randy Dockens; Chahin Pachai; Erik Portelius; Ulf Andreasson; Kaj Blennow; Holly Soares; Charles Albright; Howard H Feldman; Robert M Berman
Journal: Arch Neurol Date: 2012-11

2. Familial Alzheimer disease presenilin-1 mutations alter the active site conformation of γ-secretase.

Authors: De-Ming Chau; Christina J Crump; Jennifer C Villa; David A Scheinberg; Yue-Ming Li
Journal: J Biol Chem Date: 2012-03-29 Impact factor: 5.157

3. Loss of presenilin 1 is associated with enhanced beta-catenin signaling and skin tumorigenesis.

Authors: X Xia; S Qian; S Soriano; Y Wu; A M Fletcher; X J Wang; E H Koo; X Wu; H Zheng
Journal: Proc Natl Acad Sci U S A Date: 2001-08-21 Impact factor: 11.205

4. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo.

Authors: G Thinakaran; D R Borchelt; M K Lee; H H Slunt; L Spitzer; G Kim; T Ratovitsky; F Davenport; C Nordstedt; M Seeger; J Hardy; A I Levey; S E Gandy; N A Jenkins; N G Copeland; D L Price; S S Sisodia
Journal: Neuron Date: 1996-07 Impact factor: 17.173

5. Piperidine acetic acid based γ-secretase modulators directly bind to Presenilin-1.

Authors: Christina J Crump; Benjamin A Fish; Suita V Castro; De-Ming Chau; Natalya Gertsik; Kwangwook Ahn; Cory Stiff; Nikolay Pozdnyakov; Kelly R Bales; Douglas S Johnson; Yue-Ming Li
Journal: ACS Chem Neurosci Date: 2011-12-21 Impact factor: 4.418

6. Modulation of gamma-secretase reduces beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease.

Authors: Maria Z Kounnas; Anne M Danks; Soan Cheng; Curtis Tyree; Elizabeth Ackerman; Xulun Zhang; Kwangwook Ahn; Phuong Nguyen; Dan Comer; Long Mao; Chengzhi Yu; David Pleynet; Paul J Digregorio; Gonul Velicelebi; Kenneth A Stauderman; William T Comer; William C Mobley; Yue-Ming Li; Sangram S Sisodia; Rudolph E Tanzi; Steven L Wagner
Journal: Neuron Date: 2010-09-09 Impact factor: 17.173

7. Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1.

Authors: Y M Li; M Xu; M T Lai; Q Huang; J L Castro; J DiMuzio-Mower; T Harrison; C Lellis; A Nadin; J G Neduvelil; R B Register; M K Sardana; M S Shearman; A L Smith; X P Shi; K C Yin; J A Shafer; S J Gardell
Journal: Nature Date: 2000-06-08 Impact factor: 49.962

8. Notch1 functions as a tumor suppressor in mouse skin.

Authors: Michael Nicolas; Anita Wolfer; Kenneth Raj; J Alain Kummer; Pleasantine Mill; Mascha van Noort; Chi-chung Hui; Hans Clevers; G Paolo Dotto; Freddy Radtke
Journal: Nat Genet Date: 2003-02-18 Impact factor: 38.330

Review 9. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.

Authors: John Hardy; Dennis J Selkoe
Journal: Science Date: 2002-07-19 Impact factor: 47.728

10. Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer's disease.

Authors: Robert L Martone; Hua Zhou; Kevin Atchison; Thomas Comery; Jane Z Xu; Xinyi Huang; Xioahai Gong; Mei Jin; Anthony Kreft; Boyd Harrison; Scott C Mayer; Suzan Aschmies; Cathleen Gonzales; Margaret M Zaleska; David R Riddell; Erik Wagner; Peimin Lu; Shaiu-Ching Sun; June Sonnenberg-Reines; Aram Oganesian; Karissa Adkins; Michael W Leach; David W Clarke; Donna Huryn; Magid Abou-Gharbia; Ronald Magolda; Jonathan Bard; Glen Frick; Sangeeta Raje; S Bradley Forlow; Carrie Balliet; Michael E Burczynski; Peter H Reinhart; Hong I Wan; Menelas N Pangalos; J Steven Jacobsen
Journal: J Pharmacol Exp Ther Date: 2009-08-11 Impact factor: 4.030

44 in total

1. γ-Secretase processing and effects of γ-secretase inhibitors and modulators on long Aβ peptides in cells.

Authors: Yong Ran; Pedro E Cruz; Thomas B Ladd; Abdul H Fauq; Joo In Jung; Julian Matthews; Kevin M Felsenstein; Todd E Golde
Journal: J Biol Chem Date: 2013-12-18 Impact factor: 5.157

2. γ-Secretase Inhibitors and Modulators Induce Distinct Conformational Changes in the Active Sites of γ-Secretase and Signal Peptide Peptidase.

Authors: Natalya Gertsik; De-Ming Chau; Yue-Ming Li
Journal: ACS Chem Biol Date: 2015-06-10 Impact factor: 5.100

BMS-708,163 targets presenilin and lacks notch-sparing activity.

1. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease.

2. Familial Alzheimer disease presenilin-1 mutations alter the active site conformation of γ-secretase.

3. Loss of presenilin 1 is associated with enhanced beta-catenin signaling and skin tumorigenesis.

4. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo.

5. Piperidine acetic acid based γ-secretase modulators directly bind to Presenilin-1.

6. Modulation of gamma-secretase reduces beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease.

7. Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1.

8. Notch1 functions as a tumor suppressor in mouse skin.

Review 9. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.

10. Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer's disease.

1. γ-Secretase processing and effects of γ-secretase inhibitors and modulators on long Aβ peptides in cells.

2. γ-Secretase Inhibitors and Modulators Induce Distinct Conformational Changes in the Active Sites of γ-Secretase and Signal Peptide Peptidase.

Review 3. γ-Secretase and its modulators: Twenty years and beyond.

4. Mapping the Binding Site of BMS-708163 on γ-Secretase with Cleavable Photoprobes.

5. Unlocking truths of γ-secretase in Alzheimer's disease: what is the translational potential?

Review 6. Toward the structure of presenilin/γ-secretase and presenilin homologs.

Review 7. γ-Secretase inhibitors and modulators: Mechanistic insights into the function and regulation of γ-Secretase.

Review 8. Development and mechanism of γ-secretase modulators for Alzheimer's disease.

9. A novel high throughput 1536-well Notch1 γ -secretase AlphaLISA assay.

Review 10. Physiological and pathological roles of the γ-secretase complex.