8B5I
C-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH 7,8-dimethoxy-1,3-dimethyl-1,3-dihydro-2H-benzo[d]azepin-2-one
This is a non-PDB format compatible entry.
Summary for 8B5I
| Entry DOI | 10.2210/pdb8b5i/pdb |
| Related | 8B5G 8B5H |
| Descriptor | Bromodomain-containing protein 2, 1,2-ETHANEDIOL, 2-{2-[2-(2-{2-[2-(2-ETHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL, ... (5 entities in total) |
| Functional Keywords | inhibitor complex bromodomain, transcription |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 14282.46 |
| Authors | Chung, C. (deposition date: 2022-09-22, release date: 2022-11-30, Last modification date: 2024-05-01) |
| Primary citation | Humphreys, P.G.,Anderson, N.A.,Bamborough, P.,Baxter, A.,Chung, C.W.,Cookson, R.,Craggs, P.D.,Dalton, T.,Fournier, J.C.L.,Gordon, L.J.,Gray, H.F.,Gray, M.W.,Gregory, R.,Hirst, D.J.,Jamieson, C.,Jones, K.L.,Kessedjian, H.,Lugo, D.,McGonagle, G.,Patel, V.K.,Patten, C.,Poole, D.L.,Prinjha, R.K.,Ramirez-Molina, C.,Rioja, I.,Seal, G.,Stafford, K.A.J.,Shah, R.R.,Tape, D.,Theodoulou, N.H.,Tomlinson, L.,Ukuser, S.,Wall, I.D.,Wellaway, N.,White, G. Identification and Optimization of a Ligand-Efficient Benzoazepinone Bromodomain and Extra Terminal (BET) Family Acetyl-Lysine Mimetic into the Oral Candidate Quality Molecule I-BET432. J.Med.Chem., 65:15174-15207, 2022 Cited by PubMed Abstract: The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein-protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure-activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 () as an oral candidate quality molecule. PubMed: 36378954DOI: 10.1021/acs.jmedchem.2c01102 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.604 Å) |
Structure validation
Download full validation report
