TY - JOUR
T1 - Controlling Intramolecular Interactions in the Design of Selective, High-Affinity Ligands for the CREBBP Bromodomain
AU - Brand, Michael
AU - Clayton, James
AU - Moroglu, Mustafa
AU - Schiedel, Matthias
AU - Picaud, Sarah
AU - Bluck, Joseph P.
AU - Skwarska, Anna
AU - Bolland, Hannah
AU - Chan, Anthony K.N.
AU - Laurin, Corentine M.C.
AU - Scorah, Amy R.
AU - See, Larissa
AU - Rooney, Timothy P.C.
AU - Andrews, Katrina H.
AU - Fedorov, Oleg
AU - Perell, Gabriella
AU - Kalra, Prakriti
AU - Vinh, Kayla B.
AU - Cortopassi, Wilian A.
AU - Heitel, Pascal
AU - Christensen, Kirsten E.
AU - Cooper, Richard I.
AU - Paton, Robert S.
AU - Pomerantz, William C.K.
AU - Biggin, Philip C.
AU - Hammond, Ester M.
AU - Filippakopoulos, Panagis
AU - Conway, Stuart J.
N1 - Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society
PY - 2021/7/22
Y1 - 2021/7/22
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.1c00348
DO - 10.1021/acs.jmedchem.1c00348
M3 - Article
C2 - 34255515
AN - SCOPUS:85111207080
SN - 0022-2623
VL - 64
SP - 10102
EP - 10123
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 14
ER -
