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The Clinically Used Iron Chelator Deferasirox Is an Inhibitor of Epigenetic JumonjiC Domain-Containing Histone Demethylases

Lookup NU author(s): Professor Akane Kawamura


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© 2019 American Chemical Society.Fe(II)- and 2-oxoglutarate (2OG)-dependent JumonjiC domain-containing histone demethylases (JmjC KDMs) are "epigenetic eraser" enzymes involved in the regulation of gene expression and are emerging drug targets in oncology. We screened a set of clinically used iron chelators and report that they potently inhibit JMJD2A (KDM4A) in vitro. Mode of action investigations revealed that one compound, deferasirox, is a bona fide active site-binding inhibitor as shown by kinetic and spectroscopic studies. Synthesis of derivatives with improved cell permeability resulted in significant upregulation of histone trimethylation and potent cancer cell growth inhibition. Deferasirox was also found to inhibit human 2OG-dependent hypoxia inducible factor prolyl hydroxylase activity. Therapeutic effects of clinically used deferasirox may thus involve transcriptional regulation through 2OG oxygenase inhibition. Deferasirox might provide a useful starting point for the development of novel anticancer drugs targeting 2OG oxygenases and a valuable tool compound for investigations of KDM function.

Publication metadata

Author(s): Roatsch M, Hoffmann I, Abboud MI, Hancock RL, Tarhonskaya H, Hsu K-F, Wilkins SE, Yeh T-L, Lippl K, Serrer K, Moneke I, Ahrens TD, Robaa D, Wenzler S, Barthes NPF, Franz H, Sippl W, Lassmann S, Diederichs S, Schleicher E, Schofield CJ, Kawamura A, Schule R, Jung M

Publication type: Article

Publication status: Published

Journal: ACS Chemical Biology

Year: 2019

Volume: 14

Issue: 8

Pages: 1737-1750

Print publication date: 16/08/2019

Online publication date: 09/07/2019

Acceptance date: 09/07/2019

ISSN (print): 1554-8929

ISSN (electronic): 1554-8937

Publisher: American Chemical Society


DOI: 10.1021/acschembio.9b00289

PubMed id: 31287655


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