CCT-245737

CCT-245737 is an orally active, potent and selective CHK1 inhibitor, with an enzaymatic IC50 value of 1.4 nM against CHK1 enzyme, and exhibited >1,000-fold selectivity against CHK2 and CDK1. It potently inhibited cellular CHK1 activity (IC50 30-220nM) and enhanced gemcitabine and SN38 cytotoxicity in multiple human tumor cell lines and human tumor xenograft models. Mouse oral bioavailability was complete (100%) with extensive tumor exposure. Genotoxic-induced CHK1 activity (pS296 CHK1) and cell cycle arrest (pY15 CDK1) were inhibited both in vitro and in human tumor xenografts by CCT-245737, causing increased DNA damage and apoptosis. CCT-245737 uniquely enhanced gemcitabine antitumor activity to a greater degree than for higher doses of either agent alone, without increasing toxicity, indicating a true therapeutic advantage for this combination. Furthermore, development of a novel ELISA assay for pS296 CHK1 autophosphorylation, allowed the quantitative measurement of target inhibition in a RAS mutant human tumor xenograft of NSCLC at efficacious doses of CCT-245737. Finally, CCT-245737 also showed significant single-agent activity against a MYC-driven mouse model of B-cell lymphoma.