Department of Chemistry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto, 606-0823, Japan.
CREST, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama, 332-0012, Japan.
Chem Rec. 2018 Dec;18(12):1782-1791. doi: 10.1002/tcr.201810031. Epub 2018 Sep 11.
Lysine-specific demethylase 1 (LSD1) is one of the flavin-dependent oxidases and is involved in many cellular processes by controlling the methylation of histone H3. Recently, it has been reported that LSD1 is associated with several diseases such as cancer, metabolic disorders, and psychiatric diseases. Thus, LSD1 is an attractive molecular target for the treatment of these diseases, and its inhibitors are predicted as therapeutic agents. Although a variety of LSD1 inhibitors have been reported to date, many of them show insufficient activities and selectivity toward LSD1. Meanwhile, we identified several LSD1-selective inhibitors using target-guided synthesis strategies based on our original ideas. Our LSD1 inhibitors show not only potent LSD1-selective inhibitory activities, but also unique bioactivities both in vitro and in vivo. This account highlights our drug design concepts for and identification of LSD1-selective inhibitors.
赖氨酸特异性脱甲基酶 1（LSD1）是黄素依赖型氧化酶之一，通过控制组蛋白 H3 的甲基化参与许多细胞过程。最近，有报道称 LSD1 与癌症、代谢紊乱和精神疾病等多种疾病有关。因此，LSD1 是治疗这些疾病的有吸引力的分子靶标，其抑制剂被预测为治疗药物。尽管迄今为止已经报道了多种 LSD1 抑制剂，但其中许多对 LSD1 的活性和选择性不足。同时，我们还基于我们的原始想法，通过靶向合成策略鉴定了几种 LSD1 选择性抑制剂。我们的 LSD1 抑制剂不仅表现出有效的 LSD1 选择性抑制活性，而且在体外和体内均表现出独特的生物活性。本报告重点介绍了我们用于鉴定 LSD1 选择性抑制剂的药物设计概念。
