1. Academic Validation
  2. MK-1775, a small molecule Wee1 inhibitor, enhances anti-tumor efficacy of various DNA-damaging agents, including 5-fluorouracil

MK-1775, a small molecule Wee1 inhibitor, enhances anti-tumor efficacy of various DNA-damaging agents, including 5-fluorouracil

  • Cancer Biol Ther. 2010 Apr 1;9(7):514-22. doi: 10.4161/cbt.9.7.11115.
Hiroshi Hirai 1 Tsuyoshi Arai Megumu Okada Toshihide Nishibata Makiko Kobayashi Naoko Sakai Kazuhide Imagaki Junko Ohtani Takumi Sakai Takashi Yoshizumi Shinji Mizuarai Yoshikazu Iwasawa Hidehito Kotani
Affiliations

Affiliation

  • 1 Department of Oncology, Banyu Tsukuba Research Institute, Merck Research Laboratories, 3 Okubo, Tsukuba, Ibaraki, Japan. yrdyc661@yahoo.co.jp
Abstract

MK-1775 is a potent and selective small molecule Wee1 Inhibitor. Previously we have shown that it abrogated DNA damaged checkpoints induced by gemcitabine, carboplatin, and cisplatin and enhanced the anti-tumor efficacy of these agents selectively in p53-deficient tumor cells. MK-1775 is currently in Phase I clinical trial in combination with these anti-cancer drugs. In this study, the effects of MK-1775 on 5-fluorouracil (5-FU) and other DNA-damaging agents with different modes of action were determined. MK-1775 enhanced the cytotoxic effects of 5-FU in p53-deficient human colon Cancer cells. MK-1775 inhibited CDC2 Y15 phosphorylation in cells, abrogated DNA damaged checkpoints induced by 5-FU treatment, and caused premature entry of mitosis determined by induction of Histone H3 phosphorylation. Enhancement by MK-1775 was specific for p53-deficient cells since this compound did not sensitize p53-wild type human colon Cancer cells to 5-FU in vitro. In vivo, MK-1775 potentiated the anti-tumor efficacy of 5-FU or its prodrug, capecitabine, at tolerable doses. These enhancements were well correlated with inhibition of CDC2 phosphorylation and induction of Histone H3 phosphorylation in tumors. In addition, MK-1775 also potentiated the cytotoxic effects of pemetrexed, doxorubicin, camptothecin, and mitomycin C in vitro. These studies support the rationale for testing the combination of MK-1775 with various DNA-damaging agents in Cancer patients.

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