Identification of the KDM2/7 histone lysine demethylase subfamily inhibitor and its antiproliferative activity

Takayoshi Suzuki, Hiroki Ozasa, Yukihiro Itoh, Peng Zhan, Hideyuki Sawada, Koshiki Mino, Louise Walport, Rei Ohkubo, Akane Kawamura, Masato Yonezawa, Yuichi Tsukada, Anthony Tumber, Hidehiko Nakagawa, Makoto Hasegawa, Ryuzo Sasaki, Tamio Mizukami, Christopher J. Schofield, Naoki Miyata

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Abstract

Histone Nε-methyl lysine demethylases KDM2/7 have been identified as potential targets for cancer therapies. On the basis of the crystal structure of KDM7B, we designed and prepared a series of hydroxamate analogues bearing an alkyl chain. Enzyme assays revealed that compound 9 potently inhibits KDM2A, KDM7A, and KDM7B, with IC50s of 6.8, 0.2, and 1.2 μM, respectively. While inhibitors of KDM4s did not show any effect on cancer cells tested, the KDM2/7-subfamily inhibitor 9 exerted antiproliferative activity, indicating the potential for KDM2/7 inhibitors as anticancer agents.

Original languageEnglish
Pages (from-to)7222-7231
Number of pages10
JournalJournal of Medicinal Chemistry
Volume56
Issue number18
DOIs
Publication statusPublished - Sep 26 2013

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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    Suzuki, T., Ozasa, H., Itoh, Y., Zhan, P., Sawada, H., Mino, K., Walport, L., Ohkubo, R., Kawamura, A., Yonezawa, M., Tsukada, Y., Tumber, A., Nakagawa, H., Hasegawa, M., Sasaki, R., Mizukami, T., Schofield, C. J., & Miyata, N. (2013). Identification of the KDM2/7 histone lysine demethylase subfamily inhibitor and its antiproliferative activity. Journal of Medicinal Chemistry, 56(18), 7222-7231. https://doi.org/10.1021/jm400624b