A cell-permeable ester derivative of the JmjC histone demethylase inhibitor IOX1

ChemMedChem. 2014 Mar;9(3):566-71. doi: 10.1002/cmdc.201300428. Epub 2014 Feb 6.


The 2-oxoglutarate (2OG)-dependent Jumonji C domain (JmjC) family is the largest family of histone lysine demethylases. There is interest in developing small-molecule probes that modulate JmjC activity to investigate their biological roles. 5-Carboxy-8-hydroxyquinoline (IOX1) is the most potent broad-spectrum inhibitor of 2OG oxygenases, including the JmjC demethylases, reported to date; however, it suffers from low cell permeability. Here, we describe structure-activity relationship studies leading to the discovery of an n-octyl ester form of IOX1 with improved cellular potency (EC50 value of 100 to 4 μM). These findings are supported by in vitro inhibition and selectivity studies, docking studies, activity versus toxicity analysis in cell cultures, and intracellular uptake measurements. The n-octyl ester was found to have improved cell permeability; it was found to inhibit some JmjC demethylases in its intact ester form and to be more selective than IOX1. The n-octyl ester of IOX1 should find utility as a starting point for the development of JmjC inhibitors and as a use as a cell-permeable tool compound for studies investigating the roles of 2OG oxygenases in epigenetic regulation.

Keywords: 2-oxoglutarate (2OG) oxygenases; cell permeability; epigenetics; inhibitors; jmjc histone demethylases; structure-activity relationships.

Publication types

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

MeSH terms

  • Cell Membrane Permeability / drug effects*
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Esters / chemistry
  • Esters / pharmacology*
  • HeLa Cells
  • Humans
  • Hydroxyquinolines / chemistry
  • Hydroxyquinolines / pharmacology*
  • Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors*
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship


  • Enzyme Inhibitors
  • Esters
  • Hydroxyquinolines
  • Jumonji Domain-Containing Histone Demethylases
  • 5-carboxy-8-hydroxyquinoline