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

Abstract

Histone N(ε)-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.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 56 Issue 18 Pg. 7222-31 (Sep 26 2013) ISSN: 1520-4804 [Electronic] United States
• PMID: 23964788 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Histone Demethylases

Topics

• Antineoplastic Agents (pharmacology)
• Catalytic Domain
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (pharmacology)
• Histone Demethylases (antagonists & inhibitors, chemistry)
• Humans
• Inhibitory Concentration 50
• Models, Molecular