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

Lookup NU author(s): Professor Akane Kawamura



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


The 2-oxoglutarate (2OG)-dependent Jumonjia 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 (EC 50 value of 100 to 4a 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. © 2014 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim.

Publication metadata

Author(s): Schiller R, Scozzafava G, Tumber A, Wickens JR, Bush JT, Rai G, Lejeune C, Choi H, Yeh T-L, Chan MC, Mott BT, McCullagh JSO, Maloney DJ, Schofield CJ, Kawamura A

Publication type: Article

Publication status: Published

Journal: ChemMedChem

Year: 2014

Volume: 9

Issue: 3

Pages: 566-571

Print publication date: 01/03/2014

Online publication date: 06/02/2014

Acceptance date: 23/10/2013

Date deposited: 10/10/2019

ISSN (print): 1860-7179

ISSN (electronic): 1860-7187

Publisher: Wiley - VCH Verlag GmbH & Co. KGaA


DOI: 10.1002/cmdc.201300428

PubMed id: 24504543


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Funder referenceFunder name
British Heart Foundation
Wellcome Trust