Fluorinated tranylcypromine analogues as inhibitors of lysine-specific demethylase 1 (LSD1, KDM1A)

Bioorg Med Chem Lett. 2017 May 15;27(10):2099-2101. doi: 10.1016/j.bmcl.2017.03.081. Epub 2017 Mar 29.

Abstract

We report a series of tranylcypromine analogues containing a fluorine in the cyclopropyl ring. A number of compounds with additional m- or p-substitution of the aryl ring were micromolar inhibitors of the LSD1 enzyme. In cellular assays, the compounds inhibited the proliferation of acute myeloid leukemia cell lines. Increased levels of the biomarkers H3K4me2 and CD86 were consistent with LSD1 target engagement.

Keywords: Epigenetics; FAD-dependent enzymes; Lysine demethylase; Mechanism based inhibitors; Organofluorine compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B7-2 Antigen / metabolism
  • Biomarkers / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / toxicity
  • Halogenation
  • Histone Demethylases / antagonists & inhibitors*
  • Histone Demethylases / metabolism
  • Histones / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Tranylcypromine / analogs & derivatives*
  • Tranylcypromine / chemical synthesis
  • Tranylcypromine / toxicity

Substances

  • B7-2 Antigen
  • Biomarkers
  • Enzyme Inhibitors
  • Histones
  • Tranylcypromine
  • Histone Demethylases
  • KDM1A protein, human