Dual-target inhibitors of bromodomain and extra-terminal proteins in cancer: A review from medicinal chemistry perspectives.
Dual-target inhibitors of bromodomain and extra-terminal proteins in cancer: A review from medicinal chemistry perspectives.
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癌症中溴结构域和额外末端蛋白的双靶点抑制剂：从药物化学角度进行综述
DOI：
10.1002/med.21859
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发表时间：
2022-03
影响因子：
13.3
通讯作者：
Ouyang L
中科院分区：
文献类型：
--
作者：
Feng L;Wang G;Chen Y;He G;Liu B;Liu J;Chiang CM;Ouyang L
bromodomain -containing protein 4 （BRD4）是研究最多的bromodomain and extra-terminal （BET）家族成员，是一种染色质解读蛋白，通过与乙酰化组蛋白和非组蛋白结合来解读表观遗传密码，从而调节细胞周期、细胞分化和细胞增殖等多种细胞过程。BRD4作为一个很有前景的药物靶点，其功能与癌症、炎症、心血管疾病、肝纤维化等密切相关。目前，临床对BET抑制剂的耐药性限制了它们的应用，但当与其他靶向其他细胞成分（如PLK1、HDAC、CDK和PARP1）的肿瘤抑制剂联合使用时，已经观察到协同抗肿瘤效果。因此，设计BET溴域双靶点抑制剂是一种合理的癌症治疗策略，以提高效力，减少耐药。本文综述了BRD4的蛋白结构和生物学功能，并从药物化学的角度讨论了双BET抑制剂的研究进展。我们还讨论了目前双靶点BET抑制剂的设计和发现策略，为潜在发现其他双靶点BET抑制剂提供了见解。
Bromodomain-containing protein 4 (BRD4), as the most studied member of the bromodomain and extra-terminal (BET) family, is a chromatin reader protein interpreting epigenetic codes through binding to acetylated histones and non-histone proteins, thereby regulating diverse cellular processes including cell cycle, cell differentiation, and cell proliferation. As a promising drug target, BRD4 function is closely related to cancer, inflammation, cardiovascular disease, and liver fibrosis. Currently, clinical resistance to BET inhibitors has limited their applications but synergistic antitumor effects have been observed when used in combination with other tumor inhibitors targeting additional cellular components such as PLK1, HDAC, CDK, and PARP1. Therefore, designing dual-target inhibitors of BET bromodomains is a rational strategy in cancer treatment to increase potency and reduce drug resistance. This review summarizes the protein structures and biological functions of BRD4 and discusses recent advances of dual BET inhibitors from a medicinal chemistry perspective. We also discuss the current design and discovery strategies for dual BET inhibitors, providing insight into potential discovery of additional dual-target BET inhibitors.
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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：
8.8
作者：
Bolden JE;Tasdemir N;Dow LE;van Es JH;Wilkinson JE;Zhao Z;Clevers H;Lowe SW
通讯作者：
Lowe SW
影响因子：
--
作者：
Atkinson, Stephen J.;Soden, Peter E.;Prinjha, Rab K.
通讯作者：
Prinjha, Rab K.
影响因子：
11.4
作者：
Baumli, Sonja;Lolli, Graziano;Johnson, Louise N.
通讯作者：
Johnson, Louise N.
影响因子：
2.9
作者：
Bharatham N;Slavish PJ;Shadrick WR;Young BM;Shelat AA
通讯作者：
Shelat AA