Selective targeting of epigenetic reader domains

被引:16
作者
Greschik, Holger [1 ]
Schuele, Roland [1 ,2 ,3 ]
Guenther, Thomas [1 ]
机构
[1] Albert Ludwigs Univ Freiburg, Med Fak, Univ Klinikum Freiburg, Urol Klin & Zent Klin Forsch, Freiburg, Germany
[2] Standort Freiburg, Deutsches Konsortium Translat Krebsfor, Freiburg, Germany
[3] Albert Ludwigs Univ Freiburg, BIOSS Ctr Biol Signalling Studies, Freiburg, Germany
基金
欧洲研究理事会;
关键词
Acetyl-lysine reader; chemical probe; druggability; epigenetic reader; methyl-lysine reader; selectivity; SMALL-MOLECULE INHIBITORS; METHYL-LYSINE BINDING; CHEMICAL PROBES; DRUG DISCOVERY; BROMODOMAIN INHIBITOR; HISTONE CROTONYLATION; BET BROMODOMAINS; PHD FINGER; CBP/P300; BROMODOMAIN; BRPF1;
D O I
10.1080/17460441.2017.1303474
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Introduction: Epigenetic regulators including writers, erasers, and readers of chromatin marks have been implicated in numerous diseases and are therefore subject of intense academic and pharmaceutical research. While several small-molecule inhibitors targeting writers or erasers are either approved drugs or are currently being evaluated in clinical trials, the targeting of epigenetic readers has lagged behind. Proof-of-principle that epigenetic readers are also relevant drug targets was provided by landmark discoveries of selective inhibitors targeting the BET family of acetyl-lysine readers. More recently, high affinity chemical probes for non-BET acetyl- and methyl-lysine reader domains have also been developed. Areas covered: This article covers recent advances with the identification and validation of inhibitors and chemical probes targeting epigenetic reader domains. Issues related to epigenetic reader druggability, quality requirements for chemical probes, interpretation of cellular action, unexpected cross-talk, and future challenges are also discussed. Expert opinion: Chemical probes provide a powerful means to unravel biological functions of epigenetic readers and evaluate their potential as drug targets. To yield meaningful results, potency, selectivity, and cellular target engagement of chemical probes need to be stringently validated. Future chemical probes will probably need to fulfil additional criteria such as strict target specificity or the targeting of readers within protein complexes.
引用
收藏
页码:449 / 463
页数:15
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