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Radiosensitization of p53 Mutant Cells by PD0166285, a Novel G₂ Checkpoint Abrogator

Departments of Cancer Molecular Sciences [Y. W., J. L., Y. S.] and Cancer Pharmacology [A. K., W. R. L.], Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, Michigan 48105; Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, Michigan 48109 [J. L., T. L.]; and Onyx Pharmaceutical, Inc., Richmond, California 94806 [R. N. B.]

The lack of functional p53 in many cancer cells offers a therapeutic target for treatment. Cells lacking p53 would not be anticipated to demonstrate a G₁ checkpoint and would depend on the G₂ checkpoint to permit DNA repair prior to undergoing mitosis. We hypothesized that the G₂ checkpoint abrogator could preferentially kill p53-inactive cancer cells by removing the only checkpoint that protects these cells from premature mitosis in response to DNA damage. Because Wee1 kinase is crucial in maintaining G₂ arrest through its inhibitory phosphorylation of Cdc2, we developed a high-throughput mass screening assay and used it to screen chemical library for Wee1 inhibitors. A pyridopyrimidine class of molecule, PD0166285 was identified that inhibited Wee1 at a nanomolar concentration. At the cellular level, 0.5 µM PD0166285 dramatically inhibits irradiation-induced Cdc2 phosphorylation at the Tyr-15 and Thr-14 in seven of seven cancer cell lines tested. PD0166285 abrogates irradiation-induced G₂ arrest as shown by both biochemical markers and fluorescence-activated cell sorter analysis and significantly increases mitotic cell populations. Biologically, PD0166285 acts as a radiosensitizer to sensitize cells to radiation-induced cell death with a sensitivity enhancement ratio of 1.23 as shown by standard clonogenic assay. This radiosensitizing activity is p53 dependent with a higher efficacy in p53-inactive cells. Thus, G₂ checkpoint abrogators represent a novel class of anticancer drugs that enhance cell killing of conventional cancer therapy through the induction of premature mitosis.

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