An analog of BIX-01294 selectively inhibits a family of histone H3 lysine 9 Jumonji demethylases

J Mol Biol. 2012 Feb 24;416(3):319-27. doi: 10.1016/j.jmb.2011.12.036. Epub 2011 Dec 29.

Abstract

BIX-01294 and its analogs were originally identified and subsequently designed as potent inhibitors against histone H3 lysine 9 (H3K9) methyltransferases G9a and G9a-like protein. Here, we show that BIX-01294 and its analog E67 can also inhibit H3K9 Jumonji demethylase KIAA1718 with half-maximal inhibitory concentrations in low micromolar range. Crystallographic analysis of KIAA1718 Jumonji domain in complex with E67 indicated that the benzylated six-membered piperidine ring was disordered and exposed to solvent. Removing the moiety (generating compound E67-2) has no effect on the potency against KIAA1718 but, unexpectedly, lost inhibition against G9a-like protein by a factor of 1500. Furthermore, E67 and E67-2 have no effect on the activity against histone H3 lysine 4 (H3K4) demethylase JARID1C. Thus, our study provides a new avenue for designing and improving the potency and selectivity of inhibitors against H3K9 Jumonji demethylases over H3K9 methyltransferases and H3K4 demethylases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azepines / pharmacology*
  • Cells, Cultured
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Fibroblasts / drug effects
  • Fibroblasts / enzymology
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors
  • Histones / metabolism
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors*
  • Jumonji Domain-Containing Histone Demethylases / chemistry
  • Mice
  • Protein Structure, Tertiary
  • Quinazolines / pharmacology*

Substances

  • Azepines
  • BIX 01294
  • Enzyme Inhibitors
  • Histones
  • Quinazolines
  • Jumonji Domain-Containing Histone Demethylases
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase

Associated data

  • PDB/3U78