873697-71-3

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Biologieal

SCH 900776 is a potent and functionally selective targeting cell cycle checkpoint kinase 1 (CHK1) inhibitor with IC50 of 3 nM, 0.16 and 1.5 μM for CHK1, CDK2 and CHK2, respectively. Checkpoint kinase 1 (CHK1) is an essential serine/threonine kinase which responds to DNA damage and stalled DNA replication. CHK1 is essential for maintenance of replication fork viability during exposure to DNA antimetabolites. SCH 900776 possesses potential radiosensitization and chemosensitization activities. In addition, simultaneous addition of SCH 727965 during hydroxyurea exposure also suppressed accumulation of γ-H2AX, in a dose-dependent manner. SCH 900776 reveals an approximate EC50 of 60 nM. In direct binding studies, the Kd of SCH 900776 for the CHK1 kinase domain was determined to be 2 nM, in good line with the enzymatically determined IC50. SCH 900776 is a weak inhibitor of CDK2. 4 mg/kg SCH 900776 was sufficient to induce the γ-H2AX biomarker while 8 mg/kg led to enhanced tumor pharmacodynamic and regression responses relative to gemcitabine or SCH 900776 alone. Dose escalation of SCH 900776 (16 and 32 mg/kg) induced incremental improvements in tumor response. In addition, combination of gemcitabine at clinically relevant levels with active doses of SCH 900776 was not associated with synergistic myelosuppression in BALB/c mice. [1] SCH 900776 is originally developed by Schering-Plough. The phase I clinical trials for SCH 900776 have been completed.

Reference

[1] Guzi TJ et al. Mol Cancer Ther. 2011 Apr;10(4):591-602.