Cdc7 kinase is a key regulator of the S-phase of the cell cycle. It is known to promote the activity of DNA replication origins in eukaryotic organisms. Inhibition of Cdc7 kinase causes blockade of DNA synthesis in human cell lines. Tumor cells are then funneled into the apoptotic pathway in a p53-independent manner. Pharmacological inhibition of Cdc7 kinase can be an effective strategy for the development of oncologic therapeutics useful for treatment of cancers. PHA-767491 is a potent inhibitor of Cdc7 kinase with an IC50 value of 10 nM in the presence of 1.5 μM ATP. At 10 μM, PHA-767491 induces apoptotic cell death in multiple cancer cell types. PHA-767491 also inhibits Cdk9, a kinase involved in the phosphorylation of RNA polymerase II and in transcriptional regulation of gene expression, with an IC50 value of 34 nM.
