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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.

Original publication

DOI

10.1021/jm200640v

Type

Journal article

Journal

Journal of Medicinal Chemistry

Publication Date

10/2011

Volume

54

Pages

6761 - 6770

Addresses

Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.

Keywords

Hela Cells, Humans, Phenylethyl Alcohol, Isoxazoles, Protein-Serine-Threonine Kinases, Lysine, Nuclear Proteins, Histones, Transcription Factors, Cytotoxins, Ligands, Crystallography, X-Ray, Molecular Mimicry, Molecular Structure, Protein Structure, Tertiary, Protein Binding, Structure-Activity Relationship, Stereoisomerism, Models, Molecular, CREB-Binding Protein