While there are some differences between the CREBBP bromodomain and those found in the BET proteins, (11,27,30,41) the presence of the LPF shelf (CREBBP) and WPF shelf (BET) regions has made developing probes with high selectivity challenging. This is to enable firm conclusions to be drawn from data generated using the probes in cells and more intact systems. (40) One challenge in the development of CREBBP bromodomain ligands for use as probes is ensuring that they have sufficient selectivity over other bromodomains. (11) This study identified the key interactions required for binding to the CREBBP bromodomain, and these findings have subsequently underpinned the development of a number of other CREBBP bromodomain ligands.

(35−38) Building on a pioneering work by Zhou, who reported the first ligands for the CREBBP bromodomain, (39) we reported the first high-affinity ligands for the CREBBP/EP300 bromodomain. (27−32) While work has focused on the development of ligands for the BET bromodomains, (33) especially BRD4, as a result of their role in a number of cancers, (34) more recent work has seen the development of high-affinity ligands for non-BET bromodomains. Over the last decade, bromodomains have emerged as exciting targets in medicinal chemistry. In hypoxia (<0.1% O 2), the inhibition of the CREBBP/EP300 bromodomain results in the enhanced stabilization of HIF-1α. Cellular studies using this ligand demonstrate that the inhibition of the CREBBP/EP300 bromodomain in HCT116 colon cancer cells results in lowered levels of c-Myc and a reduction in H3K18 and H3K27 acetylation. Here, we report a work to develop a high-affinity, small-molecule ligand for the CREBBP and EP300 bromodomains that shows >100-fold selectivity over a representative member of the BET bromodomains, BRD4(1). The bromodomains of CREBBP and EP300 enable the binding of acetylated lysine residues from histones and a number of other important proteins, including p53, p73, E2F, and GATA1. They each comprise 10 domains through which they interact with >400 proteins, making them important transcriptional co-activators and key nodes in the human protein–protein interactome. CREBBP (CBP/KAT3A) and its paralogue EP300 (KAT3B) are lysine acetyltransferases (KATs) that are essential for human development.

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