Bromodomains are acetyl-lysine binding domains found in many chromatin-associated proteins. They play an important role in the epigenetic regulation of gene expression by binding selectively to acetylated lysine residues on histone tails. The BET proteins, a family of dual-bromodomain-containing transcriptional cofactors, are known to play a role in the pathogenesis of several cancers. Chemical probes for the BET bromodomains will enhance our understanding of the therapeutic potential of bromodomain-histone interaction inhibitors.Using a structure-guided design approach, we developed inhibitors of the BET bromodomains based around a 4-phenyl-3,5-dimethylisoxazole scaffold, and evaluated their activity against a panel of bromodomains. The most potent compounds inhibit the binding of BET bromodomains to histone peptides with nanomolar IC50 values, and show excellent ligand efficiency. X-ray co-crystal structures illustrated the interactions responsible for the potency and selectivity of these compounds, which represent an important chemotype in the on-going effort to develop chemical probes for epigenetic targets.

Developing chemical probes for the BET bromodomains

243rd National Meeting (2012)

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