3‑(Piperidin-4-ylmethoxy)pyridine Containing Compounds Are Potent Inhibitors of Lysine Specific Demethylase 1

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均发挥关键作用。赖氨酸特异性去甲基化酶1（Lysine specific demethylase 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过表达，LSD1已成为部分癌症的药物靶点。本研究报道了一类含3-(哌啶-4-基甲氧基)吡啶结构的化合物，其作为强效LSD1抑制剂的抑制常数（Ki）低至29 nM。此类化合物对相关单胺氧化酶A和B展现出优异的选择性（选择性比值＞160倍）。酶动力学与分子对接研究表明，这类化合物针对二甲基化H3K4底物属于竞争性抑制剂，并揭示了其可能的结合模式。该类强效LSD1抑制剂可提升细胞内H3K4甲基化水平，且对多种白血病细胞及实体瘤细胞的增殖具有显著抑制作用，半数有效浓度（EC50）低至280 nM，同时对正常细胞几乎无影响。