Data from Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents

Autor: Hidehito Kotani, Shinji Mizuarai, Takashi Yoshizumi, Takeshi Sagara, Toshihiro Sakamoto, Hiroharu Arakawa, Takumi Sakai, Jian Jiang, Tadahiro Nambu, Hiroko Oki, Kazuhiro Fukasawa, Ikuko Takahashi-Suzuki, Hiraku Itadani, Kazunori Yamanaka, Junko Ohtani, Naoki Kaneko, Toshifumi Kimura, Makiko Kobayashi, Toshihide Nishibata, Tsuyoshi Arai, Megumu Okada, Yoshikazu Iwasawa, Hiroshi Hirai
Rok vydání: 2023
DOI: 10.1158/1535-7163.c.6532227.v1
Popis: Wee1 is a tyrosine kinase that phosphorylates and inactivates CDC2 and is involved in G2 checkpoint signaling. Because p53 is a key regulator in the G1 checkpoint, p53-deficient tumors rely only on the G2 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 G2 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. [Mol Cancer Ther 2009;8(11):2992–3000]
Databáze: OpenAIRE