Abstract
Wee1 is a tyrosine kinase that phosphorylates and inactivates CDC2 and is involved in G(2) checkpoint signaling. Because p53 is a key regulator in the G(1) checkpoint, p53-deficient tumors rely only on the G(2) checkpoint after DNA damage. Hence, such tumors are selectively sensitized to DNA-damaging agents by Wee1 inhibition. Here, we report the discovery of a potent and selective small-molecule inhibitor of Wee1 kinase, MK-1775. This compound inhibits phosphorylation of CDC2 at Tyr15 (CDC2Y15), a direct substrate of Wee1 kinase in cells. MK-1775 abrogates G(2) DNA damage checkpoint, leading to apoptosis in combination with DNA-damaging chemotherapeutic agents such as gemcitabine, carboplatin, and cisplatin selectively in p53-deficient cells. In vivo, MK-1775 potentiates tumor growth inhibition by these agents, and cotreatment does not significantly increase toxicity. The enhancement of antitumor effect by MK-1775 was well correlated with inhibition of CDC2Y15 phosphorylation in tumor tissue and skin hair follicles. Our data indicate that Wee1 inhibition provides a new approach for treatment of multiple human malignancies.
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Apoptosis / drug effects
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CDC2 Protein Kinase
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Line, Tumor
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Cyclin B / metabolism
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Cyclin-Dependent Kinases
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DNA Damage*
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Drug Synergism
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Flow Cytometry
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HeLa Cells
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Humans
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Neoplasms / drug therapy*
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Neoplasms / enzymology
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Neoplasms / genetics
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Neoplasms / pathology
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Nuclear Proteins / antagonists & inhibitors*
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / pharmacology*
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Pyrazoles / administration & dosage
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Pyrazoles / pharmacology*
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Pyrimidines / administration & dosage
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Pyrimidines / pharmacology*
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Pyrimidinones
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Rats
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Rats, Inbred F344
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Rats, Nude
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Tumor Suppressor Protein p53 / deficiency*
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Tumor Suppressor Protein p53 / metabolism
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Xenograft Model Antitumor Assays
Substances
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Cell Cycle Proteins
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Cyclin B
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Nuclear Proteins
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Protein Kinase Inhibitors
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Pyrazoles
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Pyrimidines
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Pyrimidinones
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Tumor Suppressor Protein p53
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Protein-Tyrosine Kinases
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WEE1 protein, human
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CDC2 Protein Kinase
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CDK1 protein, human
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Cyclin-Dependent Kinases
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adavosertib