Histone H3 peptides incorporating modified lysine residues as lysine-specific demethylase 1 inhibitors

Bioorg Med Chem Lett. 2018 Jan 15;28(2):167-169. doi: 10.1016/j.bmcl.2017.11.035. Epub 2017 Nov 23.

Abstract

Lysine-specific demethylase 1 (LSD1) is a flavin-dependent enzyme that removes methyl groups from mono- or dimethylated lysine residues at the fourth position of histone H3. We have previously reported several histone H3 peptides containing an LSD1 inactivator motif at Lys-4. In this study, histone H3 peptides having a trans-2-phenylcyclopropylamine (PCPA), a 2,5-dihydro-1H-pyrrole, and a 1,2,3,6-tetrahydropyridine moiety at Lys-4 were prepared along with related compounds possessing a shorter side chain at the fourth position. Enzymatic assays showed that PCPA peptides containing a longer side chain, which can react with FAD in the active site, are potent LSD1-selective inhibitors.

Keywords: Inhibitor; Lysine-specific demethylase 1 (LSD1); Peptide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Histone Demethylases / antagonists & inhibitors*
  • Histone Demethylases / metabolism
  • Histones / chemistry
  • Histones / pharmacology*
  • Humans
  • Lysine / antagonists & inhibitors*
  • Lysine / metabolism
  • Molecular Structure
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Histones
  • Peptides
  • Histone Demethylases
  • KDM1A protein, human
  • Lysine