Begacestat (GSI-953) is a potent and selective gamma-secretase inhibitor (γ-secretase) that inhibits Amyloid-beta production with nanomolar potency, selectively inhibits cleavage of APP in cellular level Notch cleavage assays, reverses situational memory deficits, and can be used to study Alzheimer's disease.

endogenous Aβ:3 nM, Notch cleavage:74 nM, Aβ42:10 nM, Aβ40:6 nM

In CHO cells overexpressing human APP, Begacestat inhibited Aβ42 with an IC₅₀ of 10 nM and Aβ40 with an IC₅₀ of 6 nM after 16 hours of treatment. In HeLa cells, the IC₅₀ for endogenous Aβ inhibition was 3 nM. Begacestat has reduced potency against Notch signaling, with an IC₅₀ of 74 nM for Notch cleavage, indicating selectivity between Aβ and Notch inhibition[2].

In Tg2576 transgenic mice, oral administration (p.o.) of Begacestat resulted in a significant reduction of brain Aβ levels at 3 hours post-dose. A single 10 mg/kg dose led to a 60% reduction in Aβ40 and a 54% reduction in Aβ42 in brain tissue. In Sprague-Dawley rats, a 30 mg/kg oral dose produced a 78% reduction in brain Aβ levels after 4 hours[2].