The Clinically Used Iron Chelator Deferasirox Is an Inhibitor of Epigenetic JumonjiC Domain-Containing Histone Demethylases
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 po...
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| Veröffentlicht in: | ACS chemical biology 2019-08, Vol.14 (8), p.1737-1750 |
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| creator | Roatsch, Martin Hoffmann, Inga Abboud, Martine I Hancock, Rebecca L Tarhonskaya, Hanna Hsu, Kuo-Feng Wilkins, Sarah E Yeh, Tzu-Lan Lippl, Kerstin Serrer, Kerstin Moneke, Isabelle Ahrens, Theresa D Robaa, Dina Wenzler, Sandra Barthes, Nicolas P. F Franz, Henriette Sippl, Wolfgang Lassmann, Silke Diederichs, Sven Schleicher, Erik Schofield, Christopher J Kawamura, Akane Schüle, Roland Jung, Manfred |
| description | 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. |
| doi_str_mv | 10.1021/acschembio.9b00289 |
| format | Article |
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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.</description><identifier>ISSN: 1554-8929</identifier><identifier>EISSN: 1554-8937</identifier><identifier>DOI: 10.1021/acschembio.9b00289</identifier><identifier>PMID: 31287655</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Catalytic Domain - drug effects ; Cell Line, Tumor ; Deferasirox - pharmacology ; Demethylation - drug effects ; Enzyme Inhibitors - pharmacology ; Epigenesis, Genetic - drug effects ; Histones - metabolism ; Humans ; Iron Chelating Agents - pharmacology ; Jumonji Domain-Containing Histone Demethylases - antagonists & inhibitors ; Jumonji Domain-Containing Histone Demethylases - chemistry</subject><ispartof>ACS chemical biology, 2019-08, Vol.14 (8), p.1737-1750</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a452t-7ba15d6cf32b187bb50fbbaf1c153f2253280f6f7814759e11dead7b19dabade3</citedby><cites>FETCH-LOGICAL-a452t-7ba15d6cf32b187bb50fbbaf1c153f2253280f6f7814759e11dead7b19dabade3</cites><orcidid>0000-0003-2141-5988 ; 0000-0002-6361-7716 ; 0000-0002-9274-1433 ; 0000-0002-0290-6565 ; 0000-0002-5985-9261 ; 0000-0002-5102-3056 ; 0000-0003-1169-5082</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acschembio.9b00289$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acschembio.9b00289$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31287655$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Roatsch, Martin</creatorcontrib><creatorcontrib>Hoffmann, Inga</creatorcontrib><creatorcontrib>Abboud, Martine I</creatorcontrib><creatorcontrib>Hancock, Rebecca L</creatorcontrib><creatorcontrib>Tarhonskaya, Hanna</creatorcontrib><creatorcontrib>Hsu, Kuo-Feng</creatorcontrib><creatorcontrib>Wilkins, Sarah E</creatorcontrib><creatorcontrib>Yeh, Tzu-Lan</creatorcontrib><creatorcontrib>Lippl, Kerstin</creatorcontrib><creatorcontrib>Serrer, Kerstin</creatorcontrib><creatorcontrib>Moneke, Isabelle</creatorcontrib><creatorcontrib>Ahrens, Theresa D</creatorcontrib><creatorcontrib>Robaa, Dina</creatorcontrib><creatorcontrib>Wenzler, Sandra</creatorcontrib><creatorcontrib>Barthes, Nicolas P. 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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.</description><subject>Catalytic Domain - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Deferasirox - pharmacology</subject><subject>Demethylation - drug effects</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Epigenesis, Genetic - drug effects</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>Iron Chelating Agents - pharmacology</subject><subject>Jumonji Domain-Containing Histone Demethylases - antagonists & inhibitors</subject><subject>Jumonji Domain-Containing Histone Demethylases - chemistry</subject><issn>1554-8929</issn><issn>1554-8937</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kF1PwjAUhhujEUT_gBemf2DYdus-Ls1AmSHxBq6XdjtlJVtL2pFI_POMgHjn1TnJeZ83OQ9Cz5RMKWH0VVS-aqCT2k4zSQhLsxs0ppxHQZqFye11Z9kIPXi_JSQK4zS7R6OQsjSJOR-jn1UDOG-10ZVo2wNee6hx4azBeQOt6K3DM1DghNfOfuPCY2FwYRot9elmFZ7v9AYM9LrCn_vOmq3O8cx2Qpsgt6YfpjYbvNC-twaGsg765tAKD_4R3SnReni6zAlav89X-SJYfn0U-dsyEBFnfZBIQXkdVypkkqaJlJwoKYWiFeWhYoyHLCUqVklKo4RnQGkNok4kzWohRQ3hBLFzb-Ws9w5UuXO6E-5QUlKeTJZ_JsuLyQF6OUO7veygviK_6obA9BwY4HJr984MP_zXeASvOYRJ</recordid><startdate>20190816</startdate><enddate>20190816</enddate><creator>Roatsch, Martin</creator><creator>Hoffmann, Inga</creator><creator>Abboud, Martine I</creator><creator>Hancock, Rebecca L</creator><creator>Tarhonskaya, Hanna</creator><creator>Hsu, Kuo-Feng</creator><creator>Wilkins, Sarah E</creator><creator>Yeh, Tzu-Lan</creator><creator>Lippl, Kerstin</creator><creator>Serrer, Kerstin</creator><creator>Moneke, Isabelle</creator><creator>Ahrens, Theresa D</creator><creator>Robaa, Dina</creator><creator>Wenzler, Sandra</creator><creator>Barthes, Nicolas P. 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F</au><au>Franz, Henriette</au><au>Sippl, Wolfgang</au><au>Lassmann, Silke</au><au>Diederichs, Sven</au><au>Schleicher, Erik</au><au>Schofield, Christopher J</au><au>Kawamura, Akane</au><au>Schüle, Roland</au><au>Jung, Manfred</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Clinically Used Iron Chelator Deferasirox Is an Inhibitor of Epigenetic JumonjiC Domain-Containing Histone Demethylases</atitle><jtitle>ACS chemical biology</jtitle><addtitle>ACS Chem. Biol</addtitle><date>2019-08-16</date><risdate>2019</risdate><volume>14</volume><issue>8</issue><spage>1737</spage><epage>1750</epage><pages>1737-1750</pages><issn>1554-8929</issn><eissn>1554-8937</eissn><abstract>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.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>31287655</pmid><doi>10.1021/acschembio.9b00289</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0003-2141-5988</orcidid><orcidid>https://orcid.org/0000-0002-6361-7716</orcidid><orcidid>https://orcid.org/0000-0002-9274-1433</orcidid><orcidid>https://orcid.org/0000-0002-0290-6565</orcidid><orcidid>https://orcid.org/0000-0002-5985-9261</orcidid><orcidid>https://orcid.org/0000-0002-5102-3056</orcidid><orcidid>https://orcid.org/0000-0003-1169-5082</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Catalytic Domain - drug effects Cell Line, Tumor Deferasirox - pharmacology Demethylation - drug effects Enzyme Inhibitors - pharmacology Epigenesis, Genetic - drug effects Histones - metabolism Humans Iron Chelating Agents - pharmacology Jumonji Domain-Containing Histone Demethylases - antagonists & inhibitors Jumonji Domain-Containing Histone Demethylases - chemistry |
| title | The Clinically Used Iron Chelator Deferasirox Is an Inhibitor of Epigenetic JumonjiC Domain-Containing Histone Demethylases |
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