Progress in the Development and Application of Small Molecule Inhibitors of Bromodomain鈥揂cetyl-lysine Interactions

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• 作者：David S. Hewings ; Timothy P. C. Rooney ; Laura E. Jennings ; Duncan A. Hay ; Christopher J. Schofield ; Paul E. Brennan ; Stefan Knapp ; Stuart J. Conway
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：9393-9413
• 全文大小：1130K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

Bromodomains, protein modules that recognize and bind to acetylated lysine, are emerging as important components of cellular machinery. These acetyl-lysine (KAc) 鈥渞eader鈥?domains are part of the write鈥搑ead鈥揺rase concept that has been linked with the transfer of epigenetic information. By reading KAc marks on histones, bromodomains mediate protein鈥損rotein 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.