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

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• 作者：Fangrui Wu ; Chao Zhou ; Yuan Yao ; Liping Wei ; Zizhen Feng ; Lisheng Deng ; Yongcheng Song
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：January 14, 2016
• 年：2016
• 卷：59
• 期：1
• 页码：253-263
• 全文大小：628K
• ISSN：1520-4804

文摘

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 K_i 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.