LY3039478

LY3039478 (Crenigacestat) is an exquisitely potent inhibitor of Notch-1 intracellular domain (N1ICD) cleavage with IC50 of 1 nM, also potently inhibits mutant Notch receptor activity; inhibits N1ICD cleavage and expression of Notch-regulated genes in the tumor microenvironment in xenograft tumor models; significantly inhibits the growth of CCRCC cell lines in a concentration-dependent manne, decreases expression of Myc and cyclin A1, causes G0/G1 cell cycle arrest in CCRCC cells, demonstrates in vivo efficacy in CCRCC in mice model. Blood Cancer Phase 2 Clinical (In Vitro) :Crenigacestat (100 nM) exhibits anti-cancer activity in K07074 cells (a primary mouse liver tumor cell line) .Crenigacestat (LY3039478) decreases expression of Myc and cyclin A1 (part of the NOTCH-driven proliferative signature) in murine and human model systems. Crenigacestat (LY3039478) treatment also leads to G0/G1 cell cycle arrest in CCRCC cells. (In Vivo) :Crenigacestat (8 mg/kg, oral gavage three times a week) resulted in significantly increases survival and delayed tumor growth in independent cohorts of mice demonstrating in vivo efficacy in CCRCC.