Discovery of pyrazolo[1,5-a]pyrimidine-3-carbonitrile derivatives as a new class of histone lysine demethylase 4D (KDM4D) inhibitors

Bioorg Med Chem Lett. 2017 Jul 15;27(14):3201-3204. doi: 10.1016/j.bmcl.2017.05.002. Epub 2017 May 3.

Abstract

Herein we report the discovery of a series of new small molecule inhibitors of histone lysine demethylase 4D (KDM4D). Molecular docking was first performed to screen for new KDM4D inhibitors from various chemical databases. Two hit compounds were retrieved. Further structural optimization and structure-activity relationship (SAR) analysis were carried out to the more selective one, compound 2, which led to the discovery of several new KDM4D inhibitors. Among them, compound 10r is the most potent one with an IC50 value of 0.41±0.03μM against KDM4D. Overall, compound 10r could be taken as a good lead compound for further studies.

Keywords: Epigenetics; Histone lysine demethylase; KDM4D; Small molecule inhibitor; Structure-activity relationship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Drug Evaluation, Preclinical
  • Humans
  • Inhibitory Concentration 50
  • Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors*
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Molecular Docking Simulation
  • Nitriles / chemical synthesis
  • Nitriles / chemistry*
  • Nitriles / metabolism
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Protein Structure, Tertiary
  • Pyrazoles / chemistry*
  • Pyrimidines / chemistry*
  • Structure-Activity Relationship

Substances

  • Nitriles
  • Protein Isoforms
  • Pyrazoles
  • Pyrimidines
  • pyrazolo(1,5-a)pyrimidine
  • Jumonji Domain-Containing Histone Demethylases
  • KDM4D protein, human