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.