期刊
BIOCHEMISTRY
卷 51, 期 37, 页码 7209-7211出版社
AMER CHEMICAL SOC
DOI: 10.1021/bi301137h
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资金
- National Institutes of Health [1R01NS076117-01]
- Alzheimer Association Grant [IIRG-08-90824]
- Institutional Training Grant [T32 GM073546-01A1]
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.
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