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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• 作者：Yasushi Takemoto ; Akihiro Ito ; Hideaki Niwa ; Mutsumi Okamura ; Takashi Fujiwara ; Tomoya Hirano ; Noriko Handa ; Takashi Umehara ; Takeshi Sonoda ; Kenji Ogawa ; Mohammad Tariq ; Norikazu Nishino ; Shingo Dan ; Hiroyuki Kagechika ; Takao Yamori ; Shigeyuki Yokoyama ; Minoru Yoshida
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 28, 2016
• 年：2016
• 卷：59
• 期：8
• 页码：3650-3660
• 全文大小：672K
• 年卷期：0
• ISSN：1520-4804

文摘

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.