A small molecule modulates Jumonji histone demethylase activity and selectively inhibits cancer growth

Nat Commun. 2013;4:2035. doi: 10.1038/ncomms3035.

Abstract

The pharmacological inhibition of general transcriptional regulators has the potential to block growth through targeting multiple tumorigenic signalling pathways simultaneously. Here, using an innovative cell-based screen, we identify a structurally unique small molecule (named JIB-04) that specifically inhibits the activity of the Jumonji family of histone demethylases in vitro, in cancer cells, and in tumours in vivo. Unlike known inhibitors, JIB-04 is not a competitive inhibitor of α-ketoglutarate. In cancer, but not in patient-matched normal cells, JIB-04 alters a subset of transcriptional pathways and blocks viability. In mice, JIB-04 reduces tumour burden and prolongs survival. Importantly, we find that patients with breast tumours that overexpress Jumonji demethylases have significantly lower survival. Thus, JIB-04, a novel inhibitor of Jumonji demethylases in vitro and in vivo, constitutes a unique potential therapeutic and research tool against cancer, and validates the use of unbiased cellular screens to discover chemical modulators with disease relevance.

Publication types

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

MeSH terms

  • Aminopyridines / chemistry
  • Aminopyridines / pharmacology*
  • Aminopyridines / therapeutic use*
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Epigenesis, Genetic / drug effects
  • Histones / metabolism
  • Humans
  • Hydrazones / chemistry
  • Hydrazones / pharmacology*
  • Hydrazones / therapeutic use*
  • Inhibitory Concentration 50
  • Isomerism
  • Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors
  • Jumonji Domain-Containing Histone Demethylases / metabolism*
  • Lysine / metabolism
  • Methylation / drug effects
  • Mice
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / pathology*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Small Molecule Libraries / therapeutic use*
  • Survival Analysis
  • Transcription, Genetic / drug effects

Substances

  • Aminopyridines
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Histones
  • Hydrazones
  • JIB-04
  • Small Molecule Libraries
  • Jumonji Domain-Containing Histone Demethylases
  • Lysine