3-(Piperidin-4-ylmethoxy)pyridine Containing Compounds Are Potent Inhibitors of Lysine Specific Demethylase 1.
3-(Piperidin-4-ylmethoxy)pyridine Containing Compounds Are Potent Inhibitors of Lysine Specific Demethylase 1.
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DOI：
10.1021/acs.jmedchem.5b01361
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发表时间：
2016-01-14
影响因子：
7.3
通讯作者：
Song Y
中科院分区：
文献类型：
--
作者：
Wu F;Zhou C;Yao Y;Wei L;Feng Z;Deng L;Song Y
赖氨酸的甲基化在基因表达调节和癌症的倡议中保持着重要的作用。 3-（哌啶-4-甲基）吡啶含有化合物作为潜在的LSD1抑制剂，其Ki值低至29 nm 1个抑制剂可以增加细胞H3K4甲基化和强烈抑制几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可忽略不计。
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.