Biological and Medicinal Chemistry

Controlling Intramolecular Interactions in the Design of Selective, High-Affinity, Ligands for the CREBBP Bromodomain


CREBBP (CBP or KAT3A) and its paralogue P300 (also KAT3B) are lysine acetyltransferases (KATs) that are essential for human development. They each comprise ten domains through which they interact with over 400 proteins, making them important transcriptional co-activators, and key nodes in the human protein-protein interactome. The bromodomain of CREBBP and P300 enables binding of acetylated lysine residues from histones, and a number of other important proteins, including p53, p73, E2F and GATA1. Here we report work to develop a high affinity, small molecule, ligand for the CREBBP and P300 bromodomains [(−)-OXFBD05] that shows >100-fold selectivity over the BET bromodomains. Key to the development of (−)-OXFBD05 were fundamental studies on molecular conformation in solution and when bound to the CREBBP bromodomain. In particular, the effect of an intramolecular hydrogen bond on solution state conformation, and use of an amide bioisostere, enabled the development of (−)-OXFBD05. Initial cellular studies using this ligand demonstrate that inhibition of the CREBBP/P300 bromodomain in HCT116 colon cancer cells results in lowered levels of c-Myc, and a modest but repeatable reduction in H3K18 acetylation. In hypoxia (<0.1% O2), inhibition of the CREBBP/P300 bromodomain results in enhanced stabilization of HIF-1α. This presents an opportunity for modulating proteins that are affected by HIF-1α levels, including ACE2, which mediates SARS-CoV-2 infection of human cells.

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