Controlling Intramolecular Interactions in the Design of Selective, High-Affinity Ligands for the CREBBP Bromodomain.
Brand M., Clayton J., Moroglu M., Schiedel M., Picaud S., Bluck JP., Skwarska A., Bolland H., Chan AKN., Laurin CMC., Scorah AR., See L., Rooney TPC., Andrews KH., Fedorov O., Perell G., Kalra P., Vinh KB., Cortopassi WA., Heitel P., Christensen KE., Cooper RI., Paton RS., Pomerantz WCK., Biggin PC., Hammond EM., Filippakopoulos P., Conway SJ.
CREBBP (CBP/KAT3A) and its paralogue EP300 (KAT3B) are lysine acetyltransferases (KATs) that are essential for human development. 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. 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. Here, we report a work to develop a high-affinity, small-molecule ligand for the CREBBP and EP300 bromodomains [(-)-OXFBD05] that shows >100-fold selectivity over a representative member of the BET bromodomains, BRD4(1). 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. In hypoxia (<0.1% O2), the inhibition of the CREBBP/EP300 bromodomain results in the enhanced stabilization of HIF-1α.