Achieving clinical success with BET inhibitors as anti-cancer agents.
Achieving clinical success with BET inhibitors as anti-cancer agents.
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DOI：
10.1038/s41416-021-01321-0
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发表时间：
2021-04
影响因子：
8.8
通讯作者：
Witcher M
中科院分区：
文献类型：
--
作者：
Shorstova T;Foulkes WD;Witcher M
癌基因的转录上调是许多肿瘤进展的驱动力。然而，直到十年前，“切断”这些致癌途径的概念是一个巨大的挑战。研究表明，溴和末端外结构域(BET)基序家族的成员是一系列癌症中致癌网络的关键激活因子；它们的功能依赖于它们通过两个溴结构域(Bd1和BD2)招募到染色质。针对一个或两个溴域的BET蛋白有效抑制物(Beti)的出现，代表着朝着抑制肿瘤内致癌网络的目标迈出了重要的一步。在这里，我们讨论了BET蛋白的生物学，Beti设计的进展，并强调了预测其活性的潜在生物标记物。我们还概述了将Beti纳入联合疗法以增强其疗效的逻辑。我们认为，了解活性机制，定义预测性生物标记物，并确定有效的协同作用，是使用Beti取得临床成功的路线图。
The transcriptional upregulation of oncogenes is a driving force behind the progression of many tumours. However, until a decade ago, the concept of ‘switching off’ these oncogenic pathways represented a formidable challenge. Research has revealed that members of the bromo- and extra-terminal domain (BET) motif family are key activators of oncogenic networks in a spectrum of cancers; their function depends on their recruitment to chromatin through two bromodomains (BD1 and BD2). The advent of potent inhibitors of BET proteins (BETi), which target either one or both bromodomains, represents an important step towards the goal of suppressing oncogenic networks within tumours. Here, we discuss the biology of BET proteins, advances in BETi design and highlight potential biomarkers predicting their activity. We also outline the logic of incorporating BETi into combination therapies to enhance its efficacy. We suggest that understanding mechanisms of activity, defining predictive biomarkers and identifying potent synergies represents a roadmap for clinical success using BETi.
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DOI：
10.1158/1078-0432.ccr-12-3066
发表时间：
2013-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Cheng Z;Gong Y;Ma Y;Lu K;Lu X;Pierce LA;Thompson RC;Muller S;Knapp S;Wang J
通讯作者：
Wang J
DOI：
10.1126/science.1249830
发表时间：
2014-10-31
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Baud MGJ;Lin-Shiao E;Cardote T;Tallant C;Pschibul A;Chan KH;Zengerle M;Garcia JR;Kwan TT;Ferguson FM;Ciulli A
通讯作者：
Ciulli A
影响因子：
82.9
作者：
Dai X;Gan W;Li X;Wang S;Zhang W;Huang L;Liu S;Zhong Q;Guo J;Zhang J;Chen T;Shimizu K;Beca F;Blattner M;Vasudevan D;Buckley DL;Qi J;Buser L;Liu P;Inuzuka H;Beck AH;Wang L;Wild PJ;Garraway LA;Rubin MA;Barbieri CE;Wong KK;Muthuswamy SK;Huang J;Chen Y;Bradner JE;Wei W
通讯作者：
Wei W
影响因子：
30.8
作者：
Cameron, EE;Bachman, KE;Baylin, SB
通讯作者：
Baylin, SB
影响因子：
11.4
作者：
Dey, Anup;Yang, Wenjing;Ozato, Keiko
通讯作者：
Ozato, Keiko