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

• DOI: 10.1002/cmdc.201300428
• Publication Date: 2014-02-06T15:05:01Z
• Authors: Rachel Schiller; Giuseppe Scozzafava; Anthony Tumber; James R. Wickens; Jacob T. Bush; Ganesha Rai; Clarisse Lejeune; Hwanho Choi; Tzu‐Lan Yeh; Mun Chiang Chan; Bryan T. Mott; James S. O. McCul...; David J. Maloney; Christopher J. Sc...; Akane Kawamura
• Keywords: Demethylase; Derivative (finance)

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