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

Michael Brand, James Clayton, Mustafa Moroglu, Matthias Schiedel, Sarah Picaud, Joseph P. Bluck, Anna Skwarska, Hannah Bolland, Anthony K.N. Chan, Corentine M.C. Laurin, Amy R. Scorah, Larissa See, Timothy P.C. Rooney, Katrina H. Andrews, Oleg Fedorov, Gabriella Perell, Prakriti Kalra, Kayla B. Vinh, Wilian A. Cortopassi, Pascal HeitelKirsten E. Christensen, Richard I. Cooper, Robert S. Paton, William C.K. Pomerantz, Philip C. Biggin, Ester M. Hammond, Panagis Filippakopoulos, Stuart J. Conway

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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.

Original languageEnglish (US)
Pages (from-to)10102-10123
Number of pages22
JournalJournal of medicinal chemistry
Issue number14
StatePublished - Jul 22 2021

Bibliographical note

Funding Information:
M.B. thanks Lincoln College, Oxford, for the provision of a Berrow Foundation Scholarship. M.M. and A.R.S. thank the EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine (EP/L015838/1) and AstraZeneca, Diamond Light Source, Defense Science and Technology Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta, Takeda, UCB, and Vertex for studentship support. M.S. and P. H. were supported by the Deutsche Forschungsgemeinschaft (SCHI 1408/1-1 and HE 8639/1-1). J.B. and T.P.C.R. were supported by the EPSRC and the MRC through the Systems Approaches to Biomedical Sciences Doctoral Training Centre (EP/G037280/1) with additional support from GlaxoSmithKline for J. B. and Pfizer Neusentis for T.P.C.R. This project (J.C. and A.K.N.C.) has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement nos. 658825 and 660156. C.M.C.L. and K.H.A. thank the BBSRC and GlaxoSmithKline for studentship support (BB/M015157/1 and BB/S507003/1). W.A.C. was supported by a Science Without Borders (CAPES) scholarship. A.S., E.M.H., and S.J.C. thank the Medical Research Council (MR/N009460/1) for the award of a project grant. H.B., E.M.H., and S.J.C. thank the EPSRC for the award of a programme grant (EP/S019901/1). W.C.K.P. was supported by the National Science Foundation (CHE-1352091, CHE-1904071). P.F. thanks the Wellcome Trust (095751/Z/11/Z) and Medical Research Council (MR/N010051/1). P.C.B. thanks Lady Margaret Hall, Oxford, for research funding. S.J.C. thanks St Hugh’s College, Oxford, for research funding.

Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.


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