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

preprint
revised on 14.02.2019 and posted on 14.02.2019 by Manfred Jung, Martin Roatsch, Inga Hoffmann, Martine I. Abboud, Rebecca L. Hancock, Hanna Tarhonskaya, Kuo-Feng Hsu, Sarah E. Wilkins, Tzu-lan Yeh, Kerstin Lippl, Kerstin Serrer, Isabelle Moneke, Theresa D. Ahrens, Dina Robaa, Sandra Wenzler, Henriette Franz, Wolfgang Sippl, Silke Lassmann, Sven Diederichs, Erik Schleicher, Christopher J. Schofield, Akane Kawamura, Roland Schüle
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 similarly 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 may 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.

Funding

Deutsche Forschungsgemeinschaft (DFG); SFB992, SFB746, SFB850, SCHU688/12-1, SCHL1823/3-1, RO5526/1-1

European Research Council (AdGrant 322844)

German Cancer Consortium (DKTK Freiburg)

Cancer Research UK (C8717/A18245)

BHF Centre of Research Excellence Oxford (RE/08/004/23915)

Royal Society Dorothy Hodgkin Fellowship

Ministry of National Defense, Medical Affairs Bureau, Taiwan

Biochemical Society Krebs Memorial Award

History

Email Address of Submitting Author

manfred.jung@pharmazie.uni-freiburg.de

Institution

University of Freiburg

Country

Germany

ORCID For Submitting Author

0000-0002-6361-7716

Declaration of Conflict of Interest

None

Version Notes

1.0 Preprint 2.0 One author added

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