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

ABSTRACT: 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 p

SUBMITTER: Wu F 

PROVIDER: S-EPMC4878443 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature