Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
J Med Chem. 2012 Nov 26;55(22):9393-413. doi: 10.1021/jm300915b. Epub 2012 Sep 27.
Bromodomains, protein modules that recognize and bind to acetylated lysine, are emerging as important components of cellular machinery. These acetyl-lysine (KAc) "reader" domains are part of the write-read-erase concept that has been linked with the transfer of epigenetic information. By reading KAc marks on histones, bromodomains mediate protein-protein interactions between a diverse array of partners. There has been intense activity in developing potent and selective small molecule probes that disrupt the interaction between a given bromodomain and KAc. Rapid success has been achieved with the BET family of bromodomains, and a number of potent and selective probes have been reported. These compounds have enabled linking of the BET bromodomains with diseases, including cancer and inflammation, suggesting that bromodomains are druggable targets. Herein, we review the biology of the bromodomains and discuss the SAR for the existing small molecule probes. The biology that has been enabled by these compounds is summarized.
溴结构域是一种能够识别和结合乙酰化赖氨酸的蛋白模块，它正在成为细胞机制中的重要组成部分。这些乙酰化赖氨酸（KAc）“读取器”结构域是与表观遗传信息传递相关的“写入-读取-擦除”概念的一部分。通过读取组蛋白上的 KAc 标记，溴结构域介导了各种不同的伙伴之间的蛋白质-蛋白质相互作用。目前，开发能够有效且选择性地破坏特定溴结构域与 KAc 之间相互作用的小分子探针的活动非常活跃。BET 家族的溴结构域已经取得了快速的成功，并且已经报道了许多有效且选择性的探针。这些化合物使得 BET 溴结构域与癌症和炎症等疾病联系起来，这表明溴结构域是可成药的靶标。本文综述了溴结构域的生物学特性，并讨论了现有小分子探针的 SAR。总结了这些化合物所带来的生物学意义。
