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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.

Original publication

DOI

10.1002/cmdc.201300428

Type

Journal article

Journal

ChemMedChem

Publication Date

03/2014

Volume

9

Pages

566 - 571

Keywords

2-oxoglutarate (2OG) oxygenases, cell permeability, epigenetics, inhibitors, jmjc histone demethylases, structure-activity relationships, Cell Membrane Permeability, Cell Survival, Dose-Response Relationship, Drug, Enzyme Inhibitors, Esters, HeLa Cells, Humans, Hydroxyquinolines, Jumonji Domain-Containing Histone Demethylases, Models, Molecular, Molecular Structure, Structure-Activity Relationship