7NQJ

C-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH N-ethyl-2-(1-methyl-1H-1,2,3-triazol-4-yl)-6-(1-phenylethyl)isonicotinamide

Summary for 7NQJ

• Entry DOI: 10.2210/pdb7nqj/pdb
• Related: 7NQ5 7NQ7 7NQ8 7NQ9
• Descriptor: Bromodomain-containing protein 2, N-ethyl-2-(1-methyl-1H-1,2,3-triazol-4-yl)-6-(1-phenylethyl)isonicotinamide, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: inhibitor, histone, epigenetic reader, bromodomain, brd2, bromodomain containing protein 2, antagonist, nuclear protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 14060.19

Authors

Chung, C. (deposition date: 2021-03-01, release date: 2021-04-07, Last modification date: 2024-06-19)

Primary citation

Aylott, H.E.,Atkinson, S.J.,Bamborough, P.,Bassil, A.,Chung, C.W.,Gordon, L.,Grandi, P.,Gray, J.R.J.,Harrison, L.A.,Hayhow, T.G.,Messenger, C.,Mitchell, D.,Phillipou, A.,Preston, A.,Prinjha, R.K.,Rianjongdee, F.,Rioja, I.,Seal, J.T.,Wall, I.D.,Watson, R.J.,Woolven, J.M.,Demont, E.H.
Template-Hopping Approach Leads to Potent, Selective, and Highly Soluble Bromo and Extraterminal Domain (BET) Second Bromodomain (BD2) Inhibitors.
J.Med.Chem., 64:3249-3281, 2021

PubMed Abstract: A number of reports have recently been published describing the discovery and optimization of bromo and extraterminal inhibitors which are selective for the second bromodomain (BD2); these include our own work toward GSK046 () and GSK620 (). This paper describes our approach to mitigating the genotoxicity risk of GSK046 by replacement of the acetamide functionality with a heterocyclic ring. This was followed by a template-hopping and hybridization approach, guided by structure-based drug design, to incorporate learnings from other BD2-selective series, optimize the vector for the amide region, and explore the ZA cleft, leading to the identification of potent, selective, and bioavailable compounds (GSK452), (GSK737), and (GSK217).

PubMed: 33662213
DOI: 10.1021/acs.jmedchem.0c02156

Experimental method

X-RAY DIFFRACTION (1.734 Å)