Development and Structural Evaluation of N-Alkylated trans-2-Phenylcyclopropylamine-Based LSD1 Inhibitors

ChemMedChem. 2020 May 6;15(9):787-793. doi: 10.1002/cmdc.202000014. Epub 2020 Mar 30.

Abstract

Lysine-specific demethylase 1 (LSD1) is a flavin adenine dinucleotide (FAD)-dependent enzyme that catalyzes the demethylation of histone H3 and regulates gene expression. Because it is implicated in the regulation of diseases such as acute myeloid leukemia, potent LSD1-specific inhibitors have been pursued. Trans-2-phenylcyclopropylamine (2-PCPA)-based inhibitors featuring substitutions on the amino group have emerged, with sub-micromolar affinities toward LSD1 and high selectivities over monoamine oxidases (MAOs). We synthesized two N-alkylated 2-PCPA-based LSD1 inhibitors, S2116 and S2157, based on the previously developed S2101. S2116 and S2157 exhibited enhanced potency for LSD1 by 2.0- to 2.6-fold, as compared with S2101. In addition, they exhibited improved selectivity over MAOs. Structural analyses of LSD1 co-crystallized with S2101, S2116, S2157, or another N-alkylated inhibitor (FCPA-MPE) confirmed that the N-substituents enhance the potency of a 2-PCPA-based inhibitor of LSD1, without constituting the adduct formed with FAD.

Keywords: X-ray crystallography; chromatin; epigenetics; histone demethylase; inhibitors; nucleosomes; protein structures.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylation
  • Drug Development*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Histone Demethylases / antagonists & inhibitors*
  • Histone Demethylases / metabolism
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Tranylcypromine / chemical synthesis
  • Tranylcypromine / chemistry
  • Tranylcypromine / pharmacology*

Substances

  • Enzyme Inhibitors
  • Tranylcypromine
  • Histone Demethylases
  • KDM1A protein, human