A Selective Phenelzine Analogue Inhibitor of Histone Demethylase LSD1

ACS Chem Biol. 2014 Jun 20;9(6):1284-93. doi: 10.1021/cb500018s. Epub 2014 Apr 7.

Abstract

Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that oxidatively cleaves methyl groups from monomethyl and dimethyl Lys4 of histone H3 (H3K4Me1, H3K4Me2) and can contribute to gene silencing. This study describes the design and synthesis of analogues of a monoamine oxidase antidepressant, phenelzine, and their LSD1 inhibitory properties. A novel phenelzine analogue (bizine) containing a phenyl-butyrylamide appendage was shown to be a potent LSD1 inhibitor in vitro and was selective versus monoamine oxidases A/B and the LSD1 homologue, LSD2. Bizine was found to be effective at modulating bulk histone methylation in cancer cells, and ChIP-seq experiments revealed a statistically significant overlap in the H3K4 methylation pattern of genes affected by bizine and those altered in LSD1-/- cells. Treatment of two cancer cell lines, LNCaP and H460, with bizine conferred a reduction in proliferation rate, and bizine showed additive to synergistic effects on cell growth when used in combination with two out of five HDAC inhibitors tested. Moreover, neurons exposed to oxidative stress were protected by the presence of bizine, suggesting potential applications in neurodegenerative disease.

Publication types

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

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Survival
  • Cells, Cultured
  • DNA Methylation / drug effects
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / drug effects
  • Embryo, Mammalian / enzymology
  • Enzyme Inhibitors / pharmacology*
  • Fetus / cytology
  • Fetus / drug effects
  • Fetus / enzymology
  • Histone Demethylases / antagonists & inhibitors*
  • Histones / metabolism
  • Humans
  • Monoamine Oxidase / chemistry
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / enzymology
  • Phenelzine / analogs & derivatives*
  • Phenelzine / pharmacology
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Enzyme Inhibitors
  • Histones
  • Histone Demethylases
  • Monoamine Oxidase
  • monoamine oxidase A, human
  • KDM1A protein, human
  • Phenelzine