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

被引:19
作者
Roatsch, Martin [1 ,11 ]
Hoffmann, Inga [1 ]
Abboud, Martine, I [2 ]
Hancock, Rebecca L. [2 ]
Tarhonskaya, Hanna [2 ]
Hsu, Kuo-Feng [2 ,12 ]
Wilkins, Sarah E. [2 ]
Yeh, Tzu-Lan [2 ]
Lippl, Kerstin [2 ]
Serrer, Kerstin [3 ]
Moneke, Isabelle [4 ]
Ahrens, Theresa D. [5 ,6 ]
Robaa, Dina [7 ]
Wenzler, Sandra [1 ]
Barthes, Nicolas P. F. [1 ]
Franz, Henriette [8 ,9 ]
Sipp, Wolfgang [7 ]
Lassmann, Silke [5 ,6 ]
Diederichs, Sven [4 ,10 ]
Schleicher, Erik [3 ]
Schofield, Christopher J. [2 ]
Kawamura, Akane [2 ]
Schuele, Roland [8 ,9 ]
Jung, Manfred [1 ]
机构
[1] Albert Ludwigs Univ Freiburg, Inst Pharmaceut Sci, Albertstr 25, D-79104 Freiburg, Germany
[2] Univ Oxford, Chem Res Lab, 12 Mansfield Rd, Oxford OX1 3TA, England
[3] Albert Ludwigs Univ Freiburg, Inst Phys Chem, Albertstr 21, D-79104 Freiburg, Germany
[4] Univ Freiburg, German Canc Consortium DKTK, Fac Med, Div Canc Res,Dept Thorac Surg,Med Ctr,Partner Sit, Breisacher Str 115, D-79106 Freiburg, Germany
[5] Univ Freiburg, Inst Surg Pathol, Med Ctr, Breisacher Str 115a, D-79106 Freiburg, Germany
[6] Univ Freiburg, Fac Med, Breisacher Str 115a, D-79106 Freiburg, Germany
[7] Martin Luther Univ Halle Wittenberg, Inst Pharm, Wolfgang Langenbeck Str 4, D-06120 Halle, Saale, Germany
[8] Univ Freiburg, Med Ctr, Cent Clin Res, Breisacher Str 66, D-79106 Freiburg, Germany
[9] Univ Freiburg, Fac Med, Breisacher Str 66, D-79106 Freiburg, Germany
[10] German Canc Res Ctr, Div RNA Biol & Canc, Neuenheimer Feld 280, D-69120 Heidelberg, Germany
[11] Univ Copenhagen, Ctr Biopharmaceut, Univ Pk 2, DK-2100 Copenhagen O, Denmark
[12] Natl Def Med Ctr, Triserv Gen Hosp, Taipei 114, Taiwan
基金
欧洲研究理事会; 英国生物技术与生命科学研究理事会; 英国工程与自然科学研究理事会;
关键词
IN-VITRO; CANCER-CELLS; JMJD2A; CHROMATIN; BINDING; OXYGENASES; SUBSTRATE; STRATEGY; COMPLEX; FAMILY;
D O I
10.1021/acschembio.9b00289
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1737 / 1750
页数:14
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