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及癌症发生过程中发挥着至关重要的作用。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）甲基化水平的平衡。LSD1因其与甲基化H3K4或LSD1过表达密切相关的重要功能，成为某些癌症的药物靶点。本研究报告了含3-(哌啶-4-基甲氧基)吡啶结构的化合物作为高效LSD1抑制剂的分子设计、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具有较高的选择性（>160倍）。酶动力学和对接研究表明，它们对二甲基化H3K4底物具有竞争性抑制作用，并提出了可能的结合模式。这些高效的LSD1抑制剂能够提高细胞内H3K4甲基化水平，并强烈抑制多种白血病和实体瘤细胞的增殖，其EC50值低至280 nM，而对正常细胞的影响则可忽略不计。