PF 477736 (PF-00477736, 0.01-1 μM) abrogates the camptothecin-induced DNA damage checkpoint in a dose-dependent manner in CA46 cells. PF 477736 (180, 360, 540 nM) enhances gemcitabine-induced cytotoxicity in a time- and dose-dependent manner in HT29 cells as determined by cell survival assay. PF 477736 (360 nM) in combination with gemcitabine significantly decreases the phosphorylation of CDK1, consistent with checkpoint abrogation and cell entry into mitosis. PF 477736 (PF-00477736) poorly inhibits CDK1 activity, with Ki of 9.9 μM.
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