SCH900776

SCH900776 (MK-8776) is a potent, selective and orally bioavailable inhibitor of checkpoint kinase1 (Chk1) with an IC₅₀ of 3 nM. SCH900776 shows 50- and 500-fold selectivity over CDK2 and Chk2, respectively^[1][2]. IC50 & Target: IC50: 3 nM (Chk1), 160 nM (CDK2), 1500 nM (Chk2)^[2] In Vitro: SCH900776 (300 nM) shows potent inhibitory activities against phosphorylation at ser296-Chk1. SCH900776 (1 μM) causes a 30-fold decrease in the IC₅₀ for NSC-32065 in MDA-MB-231 cells^[1]. The K_d value of SCH 900776 for the CHK1 kinase domain is 2 nM. SCH 900776 exhibits an approximate EC₅₀ of 60 nM in cells exposure to NSC-32065. SCH 900776 induces dose-dependent suppression of CHK1 pS296 and concomitant accumulation of phospho-RPA signal in U2OS cells^[2]. In Vivo: SCH 900776 induces the γ-H2AX biomarker at 4 mg/kg (i.p.), and enhances tumor pharmacodynamic and regression responses in A2780 xenograft model. SCH 900776 (16 and 32 mg/kg, i.p.) induces incremental improvements in tumor response. Escalation of SCH 900776 dose to 20 and 50 mg/kg in combination with LY 188011 results in improvements in TTP 10× in the A2780 xenograft systems^[2].