Open AccessControlling Intramolecular Interactions in the Design of Selective, High-Affinity Ligands for the CREBBP Bromodomain
Author(s) -
Michael Brand,
James Clayton,
Mustafa Moroglu,
S. Picaud,
Joseph P. Bluck,
Anna Skwarska,
Hannah R. Bolland,
Anthony Chan,
Corentine Laurin,
Amy Scorah,
Larissa See,
Timothy P. C. Rooney,
Katrina H. Andrews,
Oleg Fedorov,
Gabriella Perell,
Prakriti Kalra,
Kayla B. Vinh,
Wilian A. Cortopassi,
Pascal Heitel,
Kirsten E. Christensen,
Richard I. Cooper,
Robert S. Paton,
William C. K. Pomerantz,
Philip C. Biggin,
Ester M. Hammond,
P. Filippakopoulos,
Stuart J. Conway
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c00348
Subject(s) - bromodomain , creb binding protein , chemistry , acetylation , brd4 , biochemistry , histone , transcription factor , gene , creb
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% O 2 ), the inhibition of the CREBBP/EP300 bromodomain results in the enhanced stabilization of HIF-1α.