2. Academic Validation
  3. Potent and selective bivalent inhibitors of BET bromodomains

Potent and selective bivalent inhibitors of BET bromodomains

  • Nat Chem Biol. 2016 Dec;12(12):1097-1104. doi: 10.1038/nchembio.2210.
Michael J Waring 1 2,  Huawei Chen 3,  Alfred A Rabow 1,  Graeme Walker 1,  Romel Bobby 1,  Scott Boiko 3,  Rob H Bradbury 1,  Rowena Callis 1,  Edwin Clark 3,  Ian Dale 1,  Danette L Daniels 4,  Austin Dulak 3,  Liz Flavell 1,  Geoff Holdgate 1,  Thomas A Jowitt 5,  Alexey Kikhney 6,  Mark McAlister 1,  Jacqui Méndez 4,  Derek Ogg 1,  Joe Patel 3,  Philip Petteruti 3,  Graeme R Robb 1,  Matthew B Robers 4,  Sakina Saif 3,  Natalie Stratton 1,  Dmitri I Svergun 6,  Wenxian Wang 3,  David Whittaker 1,  David M Wilson 1,  Yi Yao 3
Affiliations

Affiliations

  • 1 AstraZeneca, Alderley Park, UK.
  • 2 Northern Institute for Cancer Research, School of Chemistry, Newcastle University, Newcastle upon Tyne, UK.
  • 3 AstraZeneca, Waltham, Massachusetts, USA.
  • 4 Promega Corporation, Madison, Wisconsin, USA.
  • 5 Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK.
  • 6 European Molecular Biology Laboratory, Hamburg, Germany.
PMID: 27775716 DOI: 10.1038/nchembio.2210
Abstract

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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z