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

  • Biochemistry. 2012 Sep 18;51(37):7209-11. doi: 10.1021/bi301137h.
Christina J Crump  1 ,  Suita V Castro ,  Feng Wang ,  Nikolay Pozdnyakov ,  T Eric Ballard ,  Sangram S Sisodia ,  Kelly R Bales ,  Douglas S Johnson ,  Yue-Ming Li
Affiliations
  • 1. Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, United States.
PMID: 22931393 DOI: 10.1021/bi301137h
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.

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