BMS-708,163 Targets Presenilin and Lacks Notch-Sparing Activity

被引：80

作者：

Crump, Christina J. ^{[1
,2
]}

Castro, Suita V. ^{[2
]}

Wang, Feng ^{[2
]}

Pozdnyakov, Nikolay ^{[3
]}

Ballard, T. Eric ^{[3
]}

Sisodia, Sangram S. ^{[4
]}

Bales, Kelly R. ^{[3
]}

Johnson, Douglas S. ^{[3
]}

Li, Yue-Ming ^{[1
,2
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, New York, NY 10065 USA

[2] Cornell Univ, Weill Grad Sch Med Sci, Dept Pharmacol, New York, NY 10021 USA

[3] Pfizer Worldwide Res & Dev, Cambridge, MA 02139 USA

[4] Univ Chicago, Ctr Mol Neurobiol, Chicago, IL 60637 USA

来源：

BIOCHEMISTRY | 2012年 / 51卷 / 37期

基金：

美国国家卫生研究院;

关键词：

GAMMA-SECRETASE INHIBITORS; ALZHEIMERS-DISEASE; MODULATION; SKIN;

D O I：

10.1021/bi301137h

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The "Notch-sparing" gamma-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 A beta 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 gamma-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 gamma-secretase inhibitor.

引用

页码：7209 / 7211

页数：3

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