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Ref Type Journal Article
PMID (11719452)
Authors Wang Y, Li J, Booher RN, Kraker A, Lawrence T, Leopold WR, Sun Y
Title Radiosensitization of p53 mutant cells by PD0166285, a novel G(2) checkpoint abrogator.
Abstract Text 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 G(1) checkpoint and would depend on the G(2) checkpoint to permit DNA repair prior to undergoing mitosis. We hypothesized that the G(2) 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 G(2) 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 microM 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 G(2) 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, G(2) 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
PD0166285 PD0166285 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
PD0166285 WEE1 Inhibitor 6 PD0166285 inhibits WEE1 kinase activity and enhances sensitivity to radiation, potentially resulting in increased tumor cell death (PMID: 21529352, PMID: 11719452, PMID: 29147815).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TP53 mutant colorectal cancer sensitive PD0166285 Preclinical Actionable In a preclinical study, PD0166285 sensitizes colorectal cancer cells with TP53 mutation to radiation induced cell death (PMID: 11719452). 11719452