Wu Fangrui, Zhou Chao, Yao Yuan, Wei Liping, Feng Zizhen, Deng Lisheng, Song Yongcheng
Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
Dan L. Duncan Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
J Med Chem. 2016 Jan 14;59(1):253-263. doi: 10.1021/acs.jmedchem.5b01361. Epub 2015 Dec 24.
Methylation of histone lysine residues plays important roles in gene expression regulation as well as cancer initiation. Lysine specific demethylase 1 (LSD1) is responsible for maintaining balanced methylation levels at histone H3 lysine 4 (H3K4). LSD1 is a drug target for certain cancers, due to important functions of methylated H3K4 or LSD1 overexpression. We report the design, synthesis, and structure-activity relationships of 3-(piperidin-4-ylmethoxy)pyridine containing compounds as potent LSD1 inhibitors with Ki values as low as 29 nM. These compounds exhibited high selectivity (>160×) against related monoamine oxidase A and B. Enzyme kinetics and docking studies suggested they are competitive inhibitors against a dimethylated H3K4 substrate and provided a possible binding mode. The potent LSD1 inhibitors can increase cellular H3K4 methylation and strongly inhibit proliferation of several leukemia and solid tumor cells with EC50 values as low as 280 nM, while they had negligible effects on normal cells.
组蛋白赖氨酸残基的甲基化在基因表达调控以及癌症发生过程中发挥着重要作用。赖氨酸特异性去甲基化酶1（LSD1）负责维持组蛋白H3赖氨酸4（H3K4）的甲基化水平平衡。由于甲基化H3K4的重要功能或LSD1的过表达，LSD1是某些癌症的药物靶点。我们报道了含3-(哌啶-4-基甲氧基)吡啶化合物作为强效LSD1抑制剂的设计、合成及构效关系，其Ki值低至29 nM。这些化合物对相关的单胺氧化酶A和B表现出高选择性（>160倍）。酶动力学和对接研究表明它们是针对二甲基化H3K4底物的竞争性抑制剂，并提供了一种可能的结合模式。强效LSD1抑制剂可增加细胞H3K4甲基化，并强烈抑制几种白血病和实体瘤细胞的增殖，EC50值低至280 nM，而对正常细胞的影响可忽略不计。
