The Clinically Used Iron Chelator Deferasirox is an Inhibitor of Epigenetic JumonjiC Domain-Containing Histone Demethylases.
The Clinically Used Iron Chelator Deferasirox is an Inhibitor of Epigenetic JumonjiC Domain-Containing Histone Demethylases.
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DOI：
10.1021/acschembio.9b00289
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发表时间：
2019-02
影响因子：
4
通讯作者：
Martin Roatsch;I. Hoffmann;Martine I. Abboud;R. L. Hancock;Hanna Tarhonskaya;Kuo-Feng Hsu;Sarah E Wilkins;Tzu-Lan Yeh;K. Lippl;Kerstin Serrer;I. Moneke;Theresa D. Ahrens;D. Robaa;Sandra Wenzler;Nicolas P. F. Barthes;Henriette Franz;W. Sippl;S. Lassmann;S. Diederichs;E. Schleicher;C. Schofield;A. Kawamura;R. Schüle;M. Jung
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作者：
Martin Roatsch;I. Hoffmann;Martine I. Abboud;R. L. Hancock;Hanna Tarhonskaya;Kuo-Feng Hsu;Sarah E Wilkins;Tzu-Lan Yeh;K. Lippl;Kerstin Serrer;I. Moneke;Theresa D. Ahrens;D. Robaa;Sandra Wenzler;Nicolas P. F. Barthes;Henriette Franz;W. Sippl;S. Lassmann;S. Diederichs;E. Schleicher;C. Schofield;A. Kawamura;R. Schüle;M. Jung
Fe(II) 和 2-酮戊二酸 (2OG) 依赖性 JumonjiC 结构域的组蛋白去甲基酶 (JmjC KDM) 是参与基因表达调节的表观遗传擦除酶，是肿瘤学中的新兴药物靶点。我们筛选了一组临床使用的铁螯合剂，并报告它们在体外有效抑制 JMJD2A (KDM4A)。作用方式研究表明，如动力学和光谱研究所示，一种化合物地拉罗司是一种真正的活性位点结合抑制剂。具有改善的细胞渗透性的衍生物的合成导致组蛋白三甲基化的显着上调和有效的癌细胞生长抑制。地拉罗司还被发现类似地抑制人类 2OG 依赖性缺氧诱导因子脯氨酰羟化酶活性。因此，临床使用的地拉罗司的治疗效果可能涉及通过 2OG 加氧酶抑制进行转录调节。地拉罗司可能为开发针对 2OG 加氧酶的新型抗癌药物提供有用的起点，并为研究 KDM 功能提供有价值的工具化合物。
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 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.