Prexasertib

A potent, selective, ATP-competitive inhibitor of CHK1 with Ki of 0.9 nM; potently abrogates the G2-M checkpoint activated by doxorubicin in p53-deficient HeLa cells with EC50 of 9 nM; causes replication catastrophe in vitro and in vivo; shows significant tumor growth inhibition in xenograft tumor models.Lung Cancer Phase 2 Clinical (In Vitro) :Prexasertib (LY2606368) inhibits MELK (IC50=38 nM), SIK (IC50=42 nM), BRSK2 (IC50=48 nM), ARK5 (IC50=64 nM) . LY2606368 requires CDC25A and CDK2 to cause DNA damage.Prexasertib (33, 100 nM; for 7 hours) results in DNA damage during S-phase in HeLa cells.Prexasertib (8-250 nM; pre-treated for 15 minutes) inhibits CHK1 autophosphorylation (S296) and CHK2 autophosphorylation (S516) in HT-29 cells.Prexasertib (4 nM; 24 hours) results in a large shift in cell-cycle populations from G1 and G2-M to S-phase with an accompanied induction of H2AX phosphorylation in U-2 OS cells.Prexasertib (33 nM; for 12 hours) causes chromosomal fragmentation in HeLa cells. Prexasertib (100 nM; 0.5 to 9 hours) induces replication stress and depletes the pool of available RPA2 for binding to DNA. (In Vivo) :Prexasertib (LY2606368; 1-10 mg/kg; SC; twice daily for 3 days, rest 4 days; for three cycles) causes growth inhibition in tumor xenografts.Prexasertib (15 mg/kg; SC) causes CHK1 inhibition in the blood and the phosphorylation of both H2AX (S139) and RPA2 (S4/S8) .