Histones, the core proteins around which DNA is wound, are susceptible to multiple post-translational modifications, combinations of which are proposed to form a 'histone code' that is involved in regulating gene expression. One such PTM, lysine acetylation, influences recruitment of transcriptional regulators through interaction with bromodomain-containing proteins (BCPs), which 'read' lysine acetylation state. There are 61 bromodomains, found within 46 proteins; these modules are emerging important therapeutic targets and the protein-protein interactions they mediate are druggable. To develop tools that enable elucidation of cellular bromodomain function, we have designed and synthesized small molecules capable of preventing the bromodomain-acetyl-lysine interaction. Herein, the design, synthesis and application of two different acetyl-lysine mimics will be described. The optimisation of these moieties to provide potent and selective ligands for the CREB binding protein (CREBBP) and the bromodomain and extra terminal domain (BET) family of BCPs will be discussed.

Cracking the histone code: Developing inhibitors of bromodomain-acetyl-lysine interactions

245th National Meeting (2013)

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