In pharmacological testing, Avagacestat significantly lowers both plasma and brain Aβ40 levels at doses of 10 and 100 mg/kg throughout the dosing interval. After a single oral dose of 1 mg/kg, Avagacestat shows a substantial reduction in Aβ40 levels for up to 8 hours and significantly reduces CSF Aβ40 levels in rats when measured 5 hours post-administration, with doses ranging from 3 to 100 mg/kg^[1].

When used as a monotherapy at 10 mg/kg, Avagacestat has a minor effect on the growth of PC9/AB2 tumors compared to gefitinib alone. The treatment results in a slight increase in caspase 3 expression and a mild reduction in Ki-67 expression in vivo, indicating a moderate impact on tumor growth and cellular proliferation. However, when combined with gefitinib, Avagacestat leads to a marked increase in caspase 3 expression and a significant decrease in Ki-67 staining in xenograft lung cancer samples, suggesting an enhanced therapeutic effect^[3].

Avagacestat (BMS-708163) has a demonstrated IC50 of 58±23 nM for inhibiting Notch processing, which is weaker compared to its potency for inhibiting APP cleavage^[1].

In cell culture studies, Avagacestat (BMS-708163) at a concentration of 10 µM when combined with gefitinib, significantly reduces colony growth in PC9/AB2 cells. This combination treatment not only enhances the expression of active caspase 3 and PARP but also diminishes Ki-67 expression, indicating increased apoptosis and enhanced cell cycle arrest at the G1 phase. Furthermore, Avagacestat effectively downregulates the expression of Notch1, HES1, PI3K, and Akt in these cells^[3].