Uses
This compound acts as a novel Chk1 inhibitor acting as an anticancer agent.
Biological Activity
sch 900776 is a potent and selective inhibitor of cell cycle checkpoint kinase 1 (chk1), chk2 and cdk3 with ic50 value of 3 nm, 1.5μm and 0.16 μm, respectively.chk is s serine/threonine kinase that senses signal of dna damage and stalls dna replication, and also plays an essential role in the maintenance of replication fork viability during exposure to dna antimetabolites.in balb/c mice, administration of sch 900776 at a dosage of 8mg/kg after gemcitabine treatment can sufficiently induce enhanced tumor pharmacodynamic and regression responses as compared to gemcitabine or sch 900776 alone 1.
in vitro
sch 900776 blocked accumulation of the chk1 ps296 autophosphorylation in a dose-dependent manner. treatment of proliferating ws1 cells with sch 900776 was found to be associated with rapid, dose-dependent accumulation of chk1 ps345, indicating that cycling populations of normal cells induce chk1 ps345 in response to the inhibition of sch 900776 as part of a futile cycle 1.
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].
IC 50
Chk1: 3 nM (IC
50); Chk2: 1500 nM (IC
50); CDK2: 160 nM (IC
50)
References
1. guzi tj, paruch k, dwyer mp, et al. targeting the replication checkpoint using sch 900776, a potent and functionally selective chk1 inhibitor identified via high content screening. molecular cancer therapeutics. 2011;10(4):591-602.
