A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes

被引：124

作者：

Baud, Matthias G. J. ^{[1
,2
]}

Lin-Shiao, Enrique ^{[1
,2
]}

Cardote, Teresa ^{[1
]}

Tallant, Cynthia ^{[2
]}

Pschibul, Annica ^{[1
]}

Chan, Kwok-Ho ^{[1
]}

Zengerle, Michael ^{[1
]}

Garcia, Jordi R. ^{[1
]}

Kwan, Terence T. -L. ^{[2
]}

Ferguson, Fleur M. ^{[2
]}

Ciulli, Alessio ^{[1
,2
]}

机构：

[1] Univ Dundee, Coll Life Sci, Div Biol Chem & Drug Discovery, James Black Ctr, Dundee DD1 5EH, Scotland

[2] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England

来源：

SCIENCE | 2014年 / 346卷 / 6209期

基金：

英国生物技术与生命科学研究理事会; 英国惠康基金;

关键词：

INHIBITION; TARGET;

D O I：

10.1126/science.1249830

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Small molecules are useful tools for probing the biological function and therapeutic potential of individual proteins, but achieving selectivity is challenging when the target protein shares structural domains with other proteins. The Bromo and Extra-Terminal (BET) proteins have attracted interest because of their roles in transcriptional regulation, epigenetics, and cancer. The BET bromodomains (protein interaction modules that bind acetyl-lysine) have been targeted by potent small-molecule inhibitors, but these inhibitors lack selectivity for individual family members. We developed an ethyl derivative of an existing small-molecule inhibitor, I-BET/JQ1, and showed that it binds leucine/alanine mutant bromodomains with nanomolar affinity and achieves up to 540-fold selectivity relative to wild-type bromodomains. Cell culture studies showed that blockade of the first bromodomain alone is sufficient to displace a specific BETprotein, Brd4, from chromatin. Expansion of this approach could help identify the individual roles of single BETproteins in human physiology and disease.

引用

页码：638 / 641

页数：4

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