Ota Yosuke, Miyamura Shin, Araki Misaho, Itoh Yukihiro, Yasuda Shusuke, Masuda Mitsuharu, Taniguchi Tomoyuki, Sowa Yoshihiro, Sakai Toshiyuki, Itami Kenichiro, Yamaguchi Junichiro, Suzuki Takayoshi
Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamo-hangi-cho, Sakyo-ku, Kyoto 603-0823, Japan.
Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan.
Bioorg Med Chem. 2018 Feb 1;26(3):775-785. doi: 10.1016/j.bmc.2017.12.045. Epub 2018 Jan 2.
Lysine-specific demethylase 1 (LSD1) is an attractive molecular target for cancer therapy. We have previously reported potent LSD1-selective inhibitors (i.e., NCD18, NCD38, and their analogs) consisting of trans-2-phenylcyclopropylamine (PCPA) or trans-2-arylcyclopropylamine (ACPA) and a lysine moiety that could form a γ-turn structure in the active site of LSD1. Herein we report the design, synthesis and evaluation of γ-turn mimetic compounds for further improvement of LSD1 inhibitory activity and anticancer activity. Among a series of γ-turn mimetic compounds synthesized by a Mitsunobu-reaction-based amination strategy, we identified 1n as a potent and selective LSD1 inhibitor. Compound 1n induced cell cycle arrest and apoptosis through histone methylation in human lung cancer cells. The γ-turn mimetics approach should offer new insights into drug design for LSD1-selective inhibitors.
赖氨酸特异性去甲基化酶1（LSD1）是癌症治疗中一个有吸引力的分子靶点。我们之前报道了由反式-2-苯基环丙胺（PCPA）或反式-2-芳基环丙胺（ACPA）以及一个赖氨酸部分组成的强效LSD1选择性抑制剂（即NCD18、NCD38及其类似物），该赖氨酸部分可在LSD1的活性位点形成γ-转角结构。在此，我们报道了用于进一步提高LSD1抑制活性和抗癌活性的γ-转角模拟化合物的设计、合成及评估。在通过基于 Mitsunobu 反应的胺化策略合成的一系列γ-转角模拟化合物中，我们确定1n为一种强效且选择性的LSD1抑制剂。化合物1n通过组蛋白甲基化在人肺癌细胞中诱导细胞周期停滞和凋亡。γ-转角模拟方法应为LSD1选择性抑制剂的药物设计提供新的见解。
