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

   


Authors: Crump, C. J.; Castro, S. V.; Wang, F.; Pozdnyakov, N.; Ballard, T. E.; Sisodia, S. S.; Bales, K. R.; Johnson, D. S.; Li, Y. M.
Article Title: BMS-708,163 targets presenilin and lacks notch-sparing activity
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. © 2012 American Chemical Society.
Keywords: clinical trial; protein binding; hela cells; drug design; drug synthesis; chemistry; amino terminal sequence; sulfonamides; receptors, notch; clinical trials, phase ii as topic; biochemistry; catalytic domain; protein cross linking; alzheimer disease; amyloid precursor protein secretases; presenilin 1; photoaffinity labeling; presenilins; alzheimer's disease; in-phase; amyloid beta-protein precursor; alkyne; n-terminals; secretases; avagacestat; photoaffinity; drug candidates; oxadiazoles
Journal Title: Biochemistry
Volume: 51
Issue: 37
ISSN: 0006-2960
Publisher: American Chemical Society  
Date Published: 2012-09-18
Start Page: 7209
End Page: 7211
Language: English
DOI: 10.1021/bi301137h
PROVIDER: scopus
PUBMED: 22931393
PMCID: PMC3470910
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-84866411763&partnerID=40&md5=8f88b886a1e814dc1f7f4fe0c4996816
Notes: --- - "Export Date: 1 October 2012" - "CODEN: BICHA" - "Source: Scopus"
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MSK Authors
  1. Yueming Li
    132 Li
  2. Christina J Crump
    12 Crump
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