7OER
C-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH N-(2,2-diphenylethyl)-1,5-dimethyl-N-(2-(methylamino)-2-oxoethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide
This is a non-PDB format compatible entry.
Summary for 7OER
| Entry DOI | 10.2210/pdb7oer/pdb |
| Related | 7OE0 7OEP |
| Descriptor | Bromodomain-containing protein 2, N-(2,2-diphenylethyl)-1,5-dimethyl-N-[2-(methylamino)-2-oxidanylidene-ethyl]-6-oxidanylidene-pyridine-3-carboxamide, 1,2-ETHANEDIOL, ... (4 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 | 13912.03 |
| Authors | Chung, C. (deposition date: 2021-05-03, release date: 2021-07-21, Last modification date: 2024-05-01) |
| Primary citation | Rianjongdee, F.,Atkinson, S.J.,Chung, C.W.,Grandi, P.,Gray, J.R.J.,Kaushansky, L.J.,Medeiros, P.,Messenger, C.,Phillipou, A.,Preston, A.,Prinjha, R.K.,Rioja, I.,Satz, A.L.,Taylor, S.,Wall, I.D.,Watson, R.J.,Yao, G.,Demont, E.H. Discovery of a Highly Selective BET BD2 Inhibitor from a DNA-Encoded Library Technology Screening Hit. J.Med.Chem., 64:10806-10833, 2021 Cited by PubMed Abstract: Second-generation bromodomain and extra terminal (BET) inhibitors, which selectively target one of the two bromodomains in the BET proteins, have begun to emerge in the literature. These inhibitors aim to help determine the roles and functions of each domain and assess whether they can demonstrate an improved safety profile in clinical settings compared to pan-BET inhibitors. Herein, we describe the discovery of a novel BET BD2-selective chemotype using a structure-based drug design from a hit identified by DNA-encoded library technologies, showing a structural differentiation from key previously reported greater than 100-fold BD2-selective chemotypes GSK620, GSK046, and ABBV-744. Following a structure-based hypothesis for the selectivity and optimization of the physicochemical properties of the series, we identified (GSK040), an in vitro ready and in vivo capable BET BD2-inhibitor of unprecedented selectivity (5000-fold) against BET BD1, excellent selectivity against other bromodomains, and good physicochemical properties. This novel chemical probe can be added to the toolbox used in the advancement of epigenetics research. PubMed: 34251219DOI: 10.1021/acs.jmedchem.1c00412 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.602 Å) |
Structure validation
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