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

Medicinal Chemistry


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.


Schiller, Rachel; Scozzafava, Giuseppe; Tumber, Anthony; Wickens, James R; Bush, Jacob T; Rai Bantukallu, Ganesha; Lejeune, Clarisse; Choi, Hwanho; Yeh, Tzu-Lan; Chan, Mun Chiang; Mott, Bryan T; McCullagh, James S O; Maloney, David J; Schofield, Christopher J; Kawamura, Akane;


  • 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

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