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PHA-767491 is a small-molecule inhibitor of Cdc7 kinase with IC50 value of 10 nM [1].

In the process of DNA synthesis, Cdc7 kinase is critical to the activation of replication origins. It phosphorylates several subunits of mini chromosome maintenance proteins (MCMs), especially the Mcm2 at Ser40 and Ser53 sites, which constitute the replicative DNA helicase. Cdc7 is overexpressed in tumor cells and tumor specimens, therefore the Cdc7 inhibitors are developed as anticancer agents. As a small-molecule Cdc7 inhibitor, PHA-767491 exerted antitumor activity through a different mechanism than other drugs target DNA replication. PHA-767491 competed with ATP for binding to Cdc7 and showed an IC50 value of 10 nM in the presence of 1.5 μM ATP [1].

PHA-767491 is a selective inhibitor. It showed no inhibitory effect on 15 kinases when tested against a panel of 38 serine/theronine and tyrosine kinases. However, it inhibited cdk1, cdk2 and GSK-3β with 20-fold less potency. Besides that, PHA-767491 was found to have inhibitory effect on Cdk9 with IC50 value of 34 nM, which made it be regarded as a dual inhibitor of Cdk7/9 kinase. When treated to a panel of 61 human cell lines, PHA-767491 caused cell proliferation inhibition with an average IC50 value of 3.17μM. It killed cells both p53-positive and p53-negative. Among the exceptions, NHDF and MCF7 cells were resistant to PHA-767491. K562 cells were less sensitive to PHA-767491 [1].

In mice bearing implanted tumors derived from HL60 cell lines, administration of PHA-767491 at dose of 20 and 30 mg/kg twice a day reduced tumor volume dose-dependently. PHA-767491 administration also resulted in 50% tumor growth inhibition in xenograft models of A2780 ovary carcinoma, HCT-116 colon carcinoma or Mx-1 mammary adenocarcinoma [1].

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