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.
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, United States.
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Crump
authors.forename: Suita V
authors.initials: SV
authors.lastname: Castro
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Nikolay
authors.initials: N
authors.lastname: Pozdnyakov
authors.forename: T Eric
authors.initials: TE
authors.lastname: Ballard
authors.forename: Sangram S
authors.initials: SS
authors.lastname: Sisodia
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Bales
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Johnson
authors.forename: Yue-Ming
authors.initials: YM
authors.lastname: Li
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D020134:Catalytic Domain; D017322:Clinical Trials, Phase II as Topic; D006367:HeLa Cells; D006801:Humans; D010069:Oxadiazoles / Q000494:pharmacology*; D053763:Presenilins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; C554092:BMS 708163; D010069:Oxadiazoles; D053763:Presenilins; D051880:Receptors, Notch; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases