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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.
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
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
PubMed id: 31287655
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