5AD3

Bivalent binding to BET bromodomains

Summary for 5AD3

• Entry DOI: 10.2210/pdb5ad3/pdb
• Related: 5AD2
• Descriptor: BROMODOMAIN-CONTAINING PROTEIN 4, 3-methoxy-N-[2-[4-[1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-piperidyl]phenoxy]ethyl]-N-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-amine (3 entities in total)
• Functional Keywords: transcription
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Nucleus: O60885
• Total number of polymer chains: 2
• Total formula weight: 30729.34

Authors

Waring, M.J.,Chen, H.,Rabow, A.A.,Walker, G.,Bobby, R.,Boiko, S.,Bradbury, R.H.,Callis, R.,Dale, I.,Daniels, D.,Flavell, L.,Holdgate, G.,Jowitt, T.A.,Kikhney, A.,McAlister, M.,Ogg, D.,Patel, J.,Petteruti, P.,Robb, G.R.,Robers, M.,Stratton, N.,Svergun, D.I.,Wang, W.,Whittaker, D. (deposition date: 2015-08-19, release date: 2016-09-28, Last modification date: 2024-01-10)

Primary citation

Waring, M.J.,Chen, H.,Rabow, A.A.,Walker, G.,Bobby, R.,Boiko, S.,Bradbury, R.H.,Callis, R.,Clark, E.,Dale, I.,Daniels, D.L.,Dulak, A.,Flavell, L.,Holdgate, G.,Jowitt, T.A.,Kikhney, A.,Mcalister, M.,Ogg, D.,Patel, J.,Petteruti, P.,Robb, G.R.,Robers, M.B.,Saif, S.,Stratton, N.,Svergun, D.I.,Wang, W.,Whittaker, D.,Wilson, D.M.,Yao, Y.
Potent and Selective Bivalent Inhibitors of Bet Bromodomains
Nat.Chem.Biol., 12:1097-, 2016

PubMed 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 EC 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.

PubMed: 27775716
DOI: 10.1038/NCHEMBIO.2210

Experimental method

X-RAY DIFFRACTION (1.49 Å)