5KHM

The first BET bromodomain of BRD4 bound to compound 13 in a bivalent manner

Summary for 5KHM

• Entry DOI: 10.2210/pdb5khm/pdb
• Descriptor: Bromodomain-containing protein 4, (3~{R})-4-[2-[4-[1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]phenoxy]ethyl]-1,3-dimethyl-piperazin-2-one, GLYCEROL, ... (4 entities in total)
• Functional Keywords: bromodomain, transcription factor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: O60885
• Total number of polymer chains: 2
• Total formula weight: 30954.62

Authors

Patel, J. (deposition date: 2016-06-15, release date: 2016-09-21, Last modification date: 2023-09-27)

Primary citation

Bradbury, R.H.,Callis, R.,Carr, G.R.,Chen, H.,Clark, E.,Feron, L.,Glossop, S.,Graham, M.A.,Hattersley, M.,Jones, C.,Lamont, S.G.,Ouvry, G.,Patel, A.,Patel, J.,Rabow, A.A.,Roberts, C.A.,Stokes, S.,Stratton, N.,Walker, G.E.,Ward, L.,Whalley, D.,Whittaker, D.,Wrigley, G.,Waring, M.J.
Optimization of a Series of Bivalent Triazolopyridazine Based Bromodomain and Extraterminal Inhibitors: The Discovery of (3R)-4-[2-[4-[1-(3-Methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-piperidyl]phenoxy]ethyl]-1,3-dimethyl-piperazin-2-one (AZD5153).
J.Med.Chem., 59:7801-7817, 2016

PubMed Abstract: Here we report the discovery and optimization of a series of bivalent bromodomain and extraterminal inhibitors. Starting with the observation of BRD4 activity of compounds from a previous program, the compounds were optimized for BRD4 potency and physical properties. The optimized compound from this campaign exhibited excellent pharmacokinetic profile and exhibited high potency in vitro and in vivo effecting c-Myc downregulation and tumor growth inhibition in xenograft studies. This compound was selected as the development candidate, AZD5153. The series showed enhanced potency as a result of bivalent binding and a clear correlation between BRD4 activity and cellular potency.

PubMed: 27528113
DOI: 10.1021/acs.jmedchem.6b00070

Experimental method

X-RAY DIFFRACTION (1.48 Å)