3,5-dimethylisoxazoles act as acetyl-lysine-mimetic bromodomain ligands

Journal article

Histone-lysine 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-bromodomain 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 μM 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.

Authors: Hewings, D; Wang, M; Philpott, M; Fedorov, O; Uttarkar, S

• Publication status: Published
• Peer review status: Peer reviewed
• Journal: Journal of Medicinal Chemistry
• Volume: 54
• Issue: 19
• Pages: 6761–6770
• Publication date: 2011-01-01
• Edition: Publisher's version
• DOI: 10.1021/jm200640v
• EISSN: 1520-4804
• ISSN: 0022-2623
• Language: English
• Subjects: Chemistry & allied sciences; Medical sciences