American Association for Cancer Research
Browse
15357163mct090463-sup-sfig_4.pdf (86.5 kB)

Supplementary Figure 4 from Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents

Download (86.5 kB)
journal contribution
posted on 2023-03-31, 23:31 authored by Hiroshi Hirai, Yoshikazu Iwasawa, Megumu Okada, Tsuyoshi Arai, Toshihide Nishibata, Makiko Kobayashi, Toshifumi Kimura, Naoki Kaneko, Junko Ohtani, Kazunori Yamanaka, Hiraku Itadani, Ikuko Takahashi-Suzuki, Kazuhiro Fukasawa, Hiroko Oki, Tadahiro Nambu, Jian Jiang, Takumi Sakai, Hiroharu Arakawa, Toshihiro Sakamoto, Takeshi Sagara, Takashi Yoshizumi, Shinji Mizuarai, Hidehito Kotani
Supplementary Figure 4 from Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents

History

ARTICLE ABSTRACT

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]