title: Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents.
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.
authors.affiliation: Department of Oncology, Banyu Tsukuba Research Institute, Merck Research Laboratories, Tsukuba, Japan. yrdyc661@yahoo.co.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hirai
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Iwasawa
authors.forename: Megumu
authors.initials: M
authors.lastname: Okada
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Arai
authors.forename: Toshihide
authors.initials: T
authors.lastname: Nishibata
authors.forename: Makiko
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Kimura
authors.forename: Naoki
authors.initials: N
authors.lastname: Kaneko
authors.forename: Junko
authors.initials: J
authors.lastname: Ohtani
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yamanaka
authors.forename: Hiraku
authors.initials: H
authors.lastname: Itadani
authors.forename: Ikuko
authors.initials: I
authors.lastname: Takahashi-Suzuki
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Fukasawa
authors.forename: Hiroko
authors.initials: H
authors.lastname: Oki
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Nambu
authors.forename: Jian
authors.initials: J
authors.lastname: Jiang
authors.forename: Takumi
authors.initials: T
authors.lastname: Sakai
authors.forename: Hiroharu
authors.initials: H
authors.lastname: Arakawa
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Sakamoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sagara
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshizumi
authors.forename: Shinji
authors.initials: S
authors.lastname: Mizuarai
authors.forename: Hidehito
authors.initials: H
authors.lastname: Kotani
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D019926:Cyclin B / Q000378:metabolism; D018844:Cyclin-Dependent Kinases; D004249:DNA Damage; D004357:Drug Synergism; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D011744:Pyrimidinones; D051381:Rats; D011916:Rats, Inbred F344; D011923:Rats, Nude; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D018797:Cell Cycle Proteins; D019926:Cyclin B; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D016159:Tumor Suppressor Protein p53; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; C549567:adavosertib