Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents.
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.
Hirai
Hiroshi
H
Department of Oncology, Banyu Tsukuba Research Institute, Merck Research Laboratories, Tsukuba, Japan. yrdyc661@yahoo.co.jp
Iwasawa
Yoshikazu
Y
Okada
Megumu
M
Arai
Tsuyoshi
T
Nishibata
Toshihide
T
Kobayashi
Makiko
M
Kimura
Toshifumi
T
Kaneko
Naoki
N
Ohtani
Junko
J
Yamanaka
Kazunori
K
Itadani
Hiraku
H
Takahashi-Suzuki
Ikuko
I
Fukasawa
Kazuhiro
K
Oki
Hiroko
H
Nambu
Tadahiro
T
Jiang
Jian
J
Sakai
Takumi
T
Arakawa
Hiroharu
H
Sakamoto
Toshihiro
T
Sagara
Takeshi
T
Yoshizumi
Takashi
T
Mizuarai
Shinji
S
Kotani
Hidehito
H
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
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