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 IC(50) 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
• Journal: Journal of medicinal chemistry
• Volume: 54
• Issue: 19
• Pages: 6761-6770
• Publication date: 2011-10-01
• DOI: 10.1021/jm200640v
• EISSN: 1520-4804
• ISSN: 0022-2623
• Language: English
• Keywords: Protein Structure, Tertiary; Models, Molecular; Molecular Mimicry; Hela Cells; Ligands; Protein-Serine-Threonine Kinases; Isoxazoles; Humans; Cytotoxins; Crystallography, X-Ray; Structure-Activity Relationship; Phenylethyl Alcohol; Histones; CREB-Binding Protein; Lysine; Transcription Factors; Stereoisomerism; Protein Binding; Molecular Structure; Nuclear Proteins