A Cell-Permeable Ester Derivative of the JmjC Histone Demethylase Inhibitor IOX1

摘要

The 2-oxoglutarate (20G)-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 (10X1) is the most potent broad-spectrum inhibitor of 20G 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 10X1 with improved cellular potency (EC_(50) 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 10X1. The n-octyl ester of 10X1 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 20G oxygenases in epigenetic regulation.