Biochemistry · 2012 · 95 citations · 14 references
Life SciencesMedicinal ChemistryPharmacologyCell SignalingDrug DiscoverySignal TransductionAlzheimer DiseaseEnzyme InhibitionLigand BindingNeurodegenerative Disease PharmacologyNeurodegenerative Disease PharmacotherapyNotch SignalingGamma Secretase InhibitionGamma-secretase ProcessingPhase Ii Clinical Trials
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.
14
A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity
Sascha Weggen, Jason L. Eriksen, Pritam Das et al. · Nature · 2001 · 1.4K citations
Endoproteolysis of Presenilin 1 and Accumulation of Processed Derivatives In Vivo
Gopal Thinakaran, David Borchelt, Michael K. Lee et al. · Neuron · 1996 · 1K citations · Full text
Notch1 functions as a tumor suppressor in mouse skin
Michaël Nicolas, Anita Wolfer, Kenneth Raj et al. · Nature Genetics · 2003 · 972 citations · Full text
Medicine, Cancer Biology, Oncology +11
Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1
Yue‐Ming Li, Min Xu, Ming‐Tain Lai et al. · Nature · 2000 · 869 citations