tcsc0180 Avagacestat

Avagacestat (BMS-708163) is a potent inhibitor of γ-secretase, with IC₅₀s of 0.27 nM and 0.30 nM for Aβ42 and Aβ40 inhibition; Avagacestat (BMS-708163) also inhibits NICD (Notch IntraCellular Domain) with IC₅₀ of 0.84 nM and shows weak inhibition of CYP2C19, with IC₅₀ of 20 μM.

IC50 & Target: IC50: 0.27 nM (γ-secretase, Aβ42), 0.30 nM (γ-secretase, Aβ40), 20 μM (CYP2C19)^[1], 0.84 nM (NICD)^[2]

In Vitro: Avagacestat (BMS-708163) exhibits weaker potency for inhibition of Notch processing, IC₅₀=58±23 nM, as compared to its inhibition potency for APP cleavage^[1]. Avagacestat (BMS-708163) (10 µM) combined with gefitinib significantly attenuates the colony growth of PC9/AB2 cells, increases the expression of active caspase 3 and PARP and reduces the expression of Ki-67 in PC9/AB2 cells. Avagacestat (BMS-708163) induces apoptosis and enhances cell cycle arrest at the G1 phase in PC9/AB2 cells. Avagacestat (BMS-708163) treatment effectively downregulates the expression of Notch1, HES1, PI3K and Akt in PC9/AB2 cells^[3].

In Vivo: Avagacestat (BMS-708163) significantly reduces both plasma and brain Aβ40 levels relative to control at 10 and 100 mg/kg for the entire dosing interval, demonstrates significant Aβ40 lowering for 8 h after an oral dose of 1 mg/kg, and significantly lowers CSF Aβ40 levels in rats, when measured 5 h after single oral doses ranging from 3 to 100 mg/kg^[1]. Avagacestat (BMS-708163) (10 mg/kg) monotherapy has a minor inhibitory effect on PC9/AB2 tumor growth compared with gefitinib alone. BMS-708163 monotherapy results in a slight increase in caspase 3 expression as well as a mild decrease in Ki-67 expression in vivo. In the xenograft lung cancer samples treated with Avagacestat (BMS-708163) plus gefitinib, there are a marked increase in caspase 3 expression and a reduction in Ki-67 staining^[3].