Cyclic AMP response element binding protein (CREB) binding protein (CREBBP or CPB) is a transcriptional co-regulator that interacts with hundereds of protein partners through multiple protein domains. CREBBP contains a bromodomain, which is a protein module that binds to acetylated lysine an 'epigenetic' mark found in numerous proteins, including histones. To understand the role played by the bromodomain in the overall function of CREBBP we have sought to develop potent and selective ligands for the CREBBP bromodomain. These compounds bind to the bromodomain and prevent it from interacting with acetyl-lysine, impairing its function. In initial work, we identified a series of dihydroquinoxalinone-based ligands in which an intramolecular hydrogen bonds preorganised the ligands into a favourable conformation for binding to the CREBBP bromodomain. When we switched to a closely related benzodiazepinone-based series, we found that this intramolecular hydrogen bond was unfavourable for CREBBP bromodomain binding. By removing this interaction we were able to develop potent and selective CREBBP bromodomain ligands. The structure- and computationally-guided optimisation of these ligands will be presented.

Harnessing intramolecular hydrogen bonds in the design of potent and selective CREBBP bromodomain ligands

256th National Meeting (2018)

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