LY-411575

LY-411575 is a potent γ-secretase inhibitor with IC₅₀ of 0.078 nM/0.082 nM (membrane/cell-based), and also inhibits Notch S3 cleavage with an IC₅₀ of 0.39 nM. IC50 & Target:IC50: 0.078 nM (γ-secretase in membrane), 0.082 nM (γ-secretase cell-based), 0.39 nM (Notch S3 cleavage cell-based)^[1] In Vitro:LY-411575 blocks Notch activation, and results in apoptosis in primary and immortalized KS cells. LY-411,575 (500 μM) induces G2/M growth arrest SLK cells^[2].
LY411575 treatment significantly decreases the amounts of intracellular HCV RNA with IC₅₀ of 0.56 ± 0.20 μM and extracellular HCV particles. LY411575 (0-40 nM) alone or in combination with BMS-790052 (0-40 pM) decreases supernatant infectious titers in a dose-dependent manner, and is synergistic regarding production of infectious virus. LY411575 (10 μM) treatment impairs ROS production in HCVcc-infected cells^[4]. LY411575 significantly attenuates EMT by inhibiting the Notch signaling activation in vitro^[5]. In Vivo:LY-411,575 (10 mg/kg) decreases brain and plasma Aβ40 and -42 robustly when chronically administered to TgCRND8 mice^[1]. LY411,575 reduces cortical Aβ40 in young transgenic CRND8 mice (ED₅₀ appr 0.6 mg/kg) and produces significant thymus atrophy and intestinal goblet cell hyperplasia at higher doses (>3 mg/kg). The extent of intestinal goblet cell hyperplasia induced by LY411,575 (10 mg/kg) is similar in young and aged mice^[3]. LY411575 inhibits mouse proliferative vitreoretinopathy (PVR) formation in vivo^[5].