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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




Journal article


J Med Chem

Publication Date





6761 - 6770


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