3,5-Dimethylisoxazoles Act As Acetyl-lysine-mimetic Bromodomain Ligands

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• 作者：David S. Hewings ; Minghua Wang ; Martin Philpott ; Oleg Fedorov ; Sagar Uttarkar ; Panagis Filippakopoulos ; Sarah Picaud ; Chaitanya Vuppusetty ; Brian Marsden ; Stefan Knapp ; Stuart J. Conway ; Tom D. Heightman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：October 13, 2011
• 年：2011
• 卷：54
• 期：19
• 页码：6761-6770
• 全文大小：1067K
• 年卷期：v.54,no.19(October 13, 2011)
• ISSN：1520-4804

文摘

Histone鈥搇ysine acetylation is a vital chromatin post-translational modification involved in the epigenetic regulation of gene transcription. Bromodomains bind acetylated lysines, acting as readers of the histone-acetylation code. Competitive inhibitors of this interaction have antiproliferative and anti-inflammatory properties. With 57 distinct bromodomains known, the discovery of subtype-selective inhibitors of the histone鈥揵romodomain interaction is of great importance. We have identified the 3,5-dimethylisoxazole moiety as a novel acetyl-lysine bioisostere, which displaces acetylated histone-mimicking peptides from bromodomains. Using X-ray crystallographic analysis, we have determined the interactions responsible for the activity and selectivity of 4-substituted 3,5-dimethylisoxazoles against a selection of phylogenetically diverse bromodomains. By exploiting these interactions, we have developed compound 4d, which has IC₅₀ values of <5 渭M for the bromodomain-containing proteins BRD2(1) and BRD4(1). These compounds are promising leads for the further development of selective probes for the bromodomain and extra C-terminal domain (BET) family and CREBBP bromodomains.