title: Identification of Cyproheptadine as an Inhibitor of SET Domain Containing Lysine Methyltransferase 7/9 (Set7/9) That Regulates Estrogen-Dependent Transcription.
abstract: 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.
authors.affiliation: Chemical Genetics Laboratory, RIKEN , 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Takemoto
authors.affiliation: 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.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ito
authors.affiliation: RIKEN Systems and Structural Biology Center , 1-7-22 Suehiro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Niwa
authors.affiliation: Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Okamura
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU) , 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU) , 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Hirano
authors.affiliation: RIKEN Systems and Structural Biology Center , 1-7-22 Suehiro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Handa
authors.affiliation: RIKEN Systems and Structural Biology Center , 1-7-22 Suehiro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Umehara
authors.affiliation: Drug Discovery Platforms Cooperation Division, RIKEN Center for Sustainable Resource Science , 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sonoda
authors.affiliation: Chemical Genetics Laboratory, RIKEN , 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ogawa
authors.affiliation: Chemical Genetics Laboratory, RIKEN , 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.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Tariq
authors.affiliation: Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology , 2-4 Hibikino, Wakamatsu, Kitakyushu, Fukuoka 808-0196, Japan.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Nishino
authors.affiliation: Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Dan
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU) , 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
authors.affiliation: Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
authors.affiliation: RIKEN Systems and Structural Biology Center , 1-7-22 Suehiro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
authors.affiliation: 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.|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.|CREST Research Project, Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D018360:Crystallography, X-Ray; D003533:Cyproheptadine / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000737:chemistry; D004967:Estrogens / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D004967:Estrogens; D003533:Cyproheptadine; D011495:Histone-Lysine N-Methyltransferase