CCT-245737

A highly potent, selective, ATP-competitive inhibitor of Chk1 with IC50 of 1.3 nM; weak inhibition on Chk2 (IC50=2440 nM) ; inhibits genotoxic-induced CHK1 activity (pS296 CHK1) and cell cycle arrest (pY15 CDK1) both in vitro and in human tumor xenografts; showes significant single-agent activity against a MYC-driven mouse model of B-cell lymphoma; orally active.Solid Tumors Phase 1 Clinical (In Vitro) :CCT245737 (10 μM) shows >80% inhibition of a panel of 124 kinases, including ERK8, PKD1, RSK2 and RSK1 with IC50s of 130, 298, 361 and 362 nM. CCT245737 abrogates an VP-16-induced G2 checkpoint in HT29, SW620, MiaPaCa-2, and Calu6 cell lines, with IC50s ranging from 30 to 220 nM. (In Vivo) :CCT245737 (150 mg/kg p.o.) inhibits tumor growth in combination with LY 188011 (100 mg/kg iv) in HT29 colon cancer xenografts. CCT245737 (300 mg/kg, p.o.) also inhibits the LY 188011 (60 mg/kg iv) induced pSer296 CHK1 autophosphorylation at 24 h in SW620 human colon cancer xenografts. CCT245737 (150 mg/kg, p.o) alone significantly inhibits tumor growth in an Eμ-Myc mouse model of human B-cell lymphocytic leukemia.