Avagacestat (BMS-708163)

γ secretase(Aβ42),γ secretase(Aβ40)

520.88

DMSO : 96 mg/mL (184.3 mM)

Powder

BMS-708163 exhibits weaker potency for inhibition of Notch processing, IC50=58±23 nM, as compared to its inhibition potency for APP cleavage. 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. BMS-708163 induces apoptosis and enhances cell cycle arrest at the G1 phase in PC9/AB2 cells. BMS-708163 treatment effectively downregulates the expression of Notch1, HES1, PI3K and Akt in PC9/AB2 cells.

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. 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 BMS-708163 plus gefitinib, there are a marked increase in caspase 3 expression and a reduction in Ki-67 staining.

BMS708163；BMS 708163；Avagacestat

C₂₀H₁₇ClF₄N₄O₄S

1146699-66-2