1. Controlling Intramolecular Interactions in the Design of Selective, High-Affinity Ligands for the CREBBP Bromodomain
- Author
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Matthias Schiedel, Katrina H. Andrews, Corentine M.C. Laurin, Joseph P. Bluck, Stuart J. Conway, Prakriti Kalra, Panagis Filippakopoulos, James Clayton, Anthony K. N. Chan, Amy R. Scorah, Oleg Fedorov, Ester M. Hammond, Mustafa Moroglu, Kayla B. Vinh, William C. K. Pomerantz, Richard I. Cooper, Wilian A. Cortopassi, Pascal Heitel, Robert S. Paton, Anna Skwarska, Gabriella T. Perell, Kirsten E. Christensen, Larissa See, Hannah Bolland, Timothy P. C. Rooney, Sarah Picaud, Philip C. Biggin, and Michael Brand
- Subjects
BRD4 ,Lysine Acetyltransferases ,Lysine ,Ligands ,01 natural sciences ,Interactome ,Article ,Small Molecule Libraries ,03 medical and health sciences ,Structure-Activity Relationship ,Drug Discovery ,Structure–activity relationship ,Humans ,030304 developmental biology ,0303 health sciences ,Benzodiazepinones ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,HCT116 Cells ,CREB-Binding Protein ,0104 chemical sciences ,Cell biology ,Bromodomain ,Histone ,Acetylation ,Drug Design ,biology.protein ,Molecular Medicine ,E1A-Associated p300 Protein - Abstract
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 (
- Published
- 2021