Potent and selective bivalent inhibitors of BET bromodomains

Michael J Waring, Huawei Chen, Alfred A Rabow, Graeme Walker, Romel Bobby, Scott Boiko, Rob H Bradbury, Rowena Callis, Edwin Clark, Ian Dale, Danette L Daniels, Austin Dulak, Liz Flavell, Geoff Holdgate, Thomas A Jowitt, Alexey Kikhney, Mark McAlister, Jacqui Méndez, Derek Ogg, Joe PatelPhilip Petteruti, Graeme R Robb, Matthew B Robers, Sakina Saif, Natalie Stratton, Dmitri I Svergun, Wenxian Wang, David Whittaker, David M Wilson, Yi Yao

Research output: Contribution to journalArticlepeer-review


Proteins of the bromodomain and extraterminal (BET) family, in particular bromodomain-containing protein 4 (BRD4), are of great interest as biological targets. BET proteins contain two separate bromodomains, and existing inhibitors bind to them monovalently. Here we describe the discovery and characterization of probe compound biBET, capable of engaging both bromodomains simultaneously in a bivalent, in cis binding mode. The evidence provided here was obtained in a variety of biophysical and cellular experiments. The bivalent binding results in very high cellular potency for BRD4 binding and pharmacological responses such as disruption of BRD4-mediator complex subunit 1 foci with an EC50 of 100 pM. These compounds will be of considerable utility as BET/BRD4 chemical probes. This work illustrates a novel concept in ligand design-simultaneous targeting of two separate domains with a drug-like small molecule-providing precedent for a potentially more effective paradigm for developing ligands for other multi-domain proteins.

Original languageEnglish
Pages (from-to)1097-1104
Number of pages8
JournalNature chemical biology
Issue number12
Early online date24 Oct 2016
Publication statusPublished - Dec 2016


  • Journal Article


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