Development and evaluation of 4-(pyrrolidin-3-yl)benzonitrile derivatives as inhibitors of lysine specific demethylase 1

Bioorg Med Chem Lett. 2017 Oct 15;27(20):4755-4759. doi: 10.1016/j.bmcl.2017.08.052. Epub 2017 Aug 24.


As part of our ongoing efforts to develop reversible inhibitors of LSD1, we identified a series of 4-(pyrrolidin-3-yl)benzonitrile derivatives that act as successful scaffold-hops of the literature inhibitor GSK-690. The most active compound, 21g, demonstrated a Kd value of 22nM and a biochemical IC50 of 57nM. In addition, this compound displayed improved selectivity over the hERG ion channel compared to GSK-690, and no activity against the related enzymes MAO-A and B. In human THP-1 acute myeloid leukaemia cells, 21g was found to increase the expression of the surrogate cellular biomarker CD86. This work further demonstrates the versatility of scaffold-hopping asa method to develop structurally diverse, potent inhibitors of LSD1.

Keywords: Acute myeloid leukaemia; Cancer therapy; Epigenetic therapy; Epigenetics; KDM1A; LSD1; Reversible inhibitor; Stem cell differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Line, Tumor
  • Drug Design
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Histone Demethylases / antagonists & inhibitors*
  • Histone Demethylases / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Molecular Docking Simulation
  • Nitriles / chemical synthesis
  • Nitriles / chemistry*
  • Nitriles / pharmacology*
  • Protein Structure, Tertiary
  • Pyrrolidines / chemistry
  • Stereoisomerism
  • Structure-Activity Relationship


  • Enzyme Inhibitors
  • Nitriles
  • Pyrrolidines
  • benzonitrile
  • Histone Demethylases
  • KDM1A protein, human
  • pyrrolidine