Identification of potent, selective KDM5 inhibitors

Bioorg Med Chem Lett. 2016 Sep 1;26(17):4350-4. doi: 10.1016/j.bmcl.2016.07.026. Epub 2016 Jul 19.

Abstract

This communication describes the identification and optimization of a series of pan-KDM5 inhibitors derived from compound 1, a hit initially identified against KDM4C. Compound 1 was optimized to afford compound 20, a 10nM inhibitor of KDM5A. Compound 20 is highly selective for the KDM5 enzymes versus other histone lysine demethylases and demonstrates activity in a cellular assay measuring the increase in global histone 3 lysine 4 tri-methylation (H3K4me3). In addition compound 20 has good ADME properties, excellent mouse PK, and is a suitable starting point for further optimization.

Keywords: Epigenetics; Histone lysine demethylase; JARID1; KDM5.

MeSH terms

  • Animals
  • Binding Sites
  • Blotting, Western
  • Cell Line
  • Drug Discovery
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / isolation & purification
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Microsomes, Liver / enzymology
  • Models, Molecular
  • Rats
  • Retinoblastoma-Binding Protein 2 / antagonists & inhibitors*

Substances

  • Enzyme Inhibitors
  • KDM5A protein, human
  • Retinoblastoma-Binding Protein 2