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J Med Chem. 2016 Apr 28;59(8):3650-60. doi: 10.1021/acs.jmedchem.5b01732. Epub 2016 Apr 18.

Identification of Cyproheptadine as an Inhibitor of SET Domain Containing Lysine Methyltransferase 7/9 (Set7/9) That Regulates Estrogen-Dependent Transcription.

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Chemical Genetics Laboratory, RIKEN , 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science , 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
RIKEN Systems and Structural Biology Center , 1-7-22 Suehiro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.
Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550, Japan.
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU) , 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
Drug Discovery Platforms Cooperation Division, RIKEN Center for Sustainable Resource Science , 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Graduate School of Science and Engineering, Saitama University , 645 Shimo-Okubo, Sakura-ku, Saitama 338-8570, Japan.
Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology , 2-4 Hibikino, Wakamatsu, Kitakyushu, Fukuoka 808-0196, Japan.
CREST Research Project, Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan.


SET domain containing lysine methyltransferase 7/9 (Set7/9), a histone lysine methyltransferase (HMT), also methylates non-histone proteins including estrogen receptor (ER) α. ERα methylation by Set7/9 stabilizes ERα and activates its transcriptional activities, which are involved in the carcinogenesis of breast cancer. We identified cyproheptadine, a clinically approved antiallergy drug, as a Set7/9 inhibitor in a high-throughput screen using a fluorogenic substrate-based HMT assay. Kinetic and X-ray crystallographic analyses revealed that cyproheptadine binds in the substrate-binding pocket of Set7/9 and inhibits its enzymatic activity by competing with the methyl group acceptor. Treatment of human breast cancer cells (MCF7 cells) with cyproheptadine decreased the expression and transcriptional activity of ERα, thereby inhibiting estrogen-dependent cell growth. Our findings suggest that cyproheptadine can be repurposed for breast cancer treatment or used as a starting point for the discovery of an anti-hormone breast cancer drug through lead optimization.

[Indexed for MEDLINE]

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