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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / drug therapy
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism
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Amyloid Precursor Protein Secretases / antagonists & inhibitors
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Amyloid Precursor Protein Secretases / genetics
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Amyloid Precursor Protein Secretases / metabolism
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism*
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Catalytic Domain
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Clinical Trials, Phase II as Topic
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HeLa Cells
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Humans
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Oxadiazoles / pharmacology*
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Presenilins / antagonists & inhibitors*
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Presenilins / genetics
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Presenilins / metabolism
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Protein Binding / drug effects
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Receptors, Notch / genetics
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Receptors, Notch / metabolism*
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Sulfonamides / pharmacology*
Substances
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APP protein, human
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Amyloid beta-Protein Precursor
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BMS 708163
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Oxadiazoles
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Presenilins
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Receptors, Notch
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Sulfonamides
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Amyloid Precursor Protein Secretases