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

J Med Chem. 2016 Jan 14;59(1):253-263. doi: 10.1021/acs.jmedchem.5b01361. Epub 2015 Dec 24.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Discovery
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Histone Demethylases / antagonists & inhibitors*
  • Histone Demethylases / genetics
  • Histones / metabolism
  • Humans
  • Kinetics
  • Methylation
  • Models, Molecular
  • Molecular Docking Simulation
  • Monoamine Oxidase Inhibitors / chemical synthesis
  • Monoamine Oxidase Inhibitors / pharmacology
  • Piperidines / chemical synthesis*
  • Piperidines / pharmacology*
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacology*
  • Structure-Activity Relationship
  • Substrate Specificity


  • 3-(piperidin-4-ylmethoxy)pyridine
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Histones
  • Monoamine Oxidase Inhibitors
  • Piperidines
  • Pyridines
  • Histone Demethylases
  • KDM1A protein, human