Bromodomains are acetyl-lysine recognition domains that mediate protein-protein interactions, often between histones and transcriptional machinery, playing an important role in the epigenetic transfer of information. Bromodomain-containing proteins play fundamental cellular roles, and show association with particular diseases including psychological diseases, obesity, inflammation and cancer [1, 2]. This wide range of biological roles emphasizes the importance of developing small molecule probes to assist in gaining a better understanding of bromodomain function in vivo. Many protein-protein interactions are challenging to inhibit, because their interfaces are often heavily solvent-exposed, cover large areas, are structurally featureless and poorly defined. Conversely, bromodomains have a well-defined binding pocket that displays characteristic interactions with acetylated lysine residues. Consequently these recognition domains have proved ligandable, with a range of ligands for the BET sub-family of bromodomains reported in the literature. Work within this group has led to the development of nanomolar potent inhibitors of the BET bromodomains. Here we report that these compounds have antiproliferative activity in a variety of cancer types and a promising profile in the NCI60 panel. We have synthesized a collection of analogues to understand the scope of SAR in the WPF region of the bromodomains, with the aim of increasing compound potency. Further optimization is being carried out to improve the physical and pharmacokinetic properties of this series of compounds, to develop a probe compound for use in animal models. References  [1] Hewings et al. J. Med. Chem. 2012 , 55(22):9393-9413.[2] Jennings et al. Future Med. Chem. 2014 , 6(2):179-204.

Optimizing in vivo probes for the BET bromodomains

248th National Meeting (2014)

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