LY2603618

A potent and selective small molecule inhibitor of Chk1 (IC50= 7 nM) ; promotes impaired DNA synthesis and elevates H2A.X phosphorylation indicative of DNA damage and premature entry into mitosis.Pancreatic Cancer Phase 2 Discontinued (In Vitro) :Rabusertib (LY2603618) is a highly effective inhibitor of multiple aspects of Chk1 biology. Rabusertib (LY2603618) is tested against a panel of 51 diverse protein kinases in vitro. With an IC50 of 7 nM for Chk1, Rabusertib (LY2603618) is approximately 100-fold more potent against Chk1 than against any of the other protein kinases evaluated (PDK1, IC50=893 nM, others >1000 nM) . Rabusertib (LY2603618) effectively reduced Chk1 autophosphorylation with an EC50 of 430 nM. Inhibition of Chk1 by Rabusertib (LY2603618) also effectively abrogated the G2/M DNA damage checkpoint in cells treated with DNA damaging agents. Treatment of cells with Rabusertib (LY2603618) produced a cellular phenotype similar to that reported for depletion of Chk1 by RNAi. Inhibition of intracellular Chk1 by Rabusertib (LY2603618) results in impaired DNA synthesis, elevated H2A.X phosphorylation indicative of DNA damage and premature entry into mitosis. Treatments of the SK-N-BE (2) cells with variable concentrations of Rabusertib (LY2603618) results in dose-dependent inhibition of cell growth determined by MTT assays with an IC50 of 10.81 μM.