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

Overview

Journal ChemMedChem

Specialties Chemistry
Pharmacology

Date 2014 Feb 8

PMID 24504543

Citations 28

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 McCullagh

David J Maloney

Christopher J Schofield

Akane Kawamura

Affiliations

Soon will be listed here.

Abstract

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.

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