Rhodium(III)-Based Inhibitor of the JMJD3-H3K27me3 Interaction and Modulator of the Inflammatory Response

Inorg Chem. 2018 Nov 19;57(22):14023-14026. doi: 10.1021/acs.inorgchem.8b02256. Epub 2018 Oct 30.

Abstract

We describe in this study a rhodium(III) complex 1 as a new JMJD3 inhibitor and proinflammatory mediator. Complex 1 selectively inhibited the demethylation of H3K27me3 over other similar substrates, indicating its selectivity for JMJD3 over other histone demethylases, including JMJD2D and KDM5A. In terms of mechanism, complex 1 inhibited the JMJD3-H3K27me3 interaction in mouse macrophage cells and down-regulated the expression of TNF-α. To our knowledge, complex 1 is the first metal-based inhibitor of JMJD3 activity and only the second class of JMJD3 inhibitor reported overall.

MeSH terms

  • Animals
  • Coordination Complexes / chemistry
  • Coordination Complexes / pharmacology*
  • Histones / metabolism*
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors*
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Ligands
  • Methylation / drug effects
  • Mice
  • Protein Binding / drug effects
  • RAW 264.7 Cells
  • Rhodium / chemistry*
  • Structure-Activity Relationship
  • Transition Temperature

Substances

  • Coordination Complexes
  • Histones
  • Ligands
  • Rhodium
  • Jumonji Domain-Containing Histone Demethylases
  • KDM6B protein, human