4BW2
The first bromodomain of human BRD4 in complex with 3,5 dimethylisoxaxole ligand
Summary for 4BW2
| Entry DOI | 10.2210/pdb4bw2/pdb |
| Related | 4BW1 4BW3 4BW4 |
| Descriptor | BROMODOMAIN-CONTAINING PROTEIN 4, 1,2-ETHANEDIOL, 4-((2-(TERT-BUTYL)PHENYL)AMINO)-7-(3,5-dimethylisoxazol-4-yl)-1,8-naphthyridine-3-carboxylic acid, ... (4 entities in total) |
| Functional Keywords | transcription, inhibitor, histone, epigenetic reader, antagonist |
| Biological source | HOMO SAPIENS (HUMAN) |
| Cellular location | Nucleus: O60885 |
| Total number of polymer chains | 1 |
| Total formula weight | 15577.92 |
| Authors | Chung, C.,Mirguet, O.,Lamotte, Y.,Bamborough, P.,Delannee, D.,Bouillot, A.,Gellibert, F.,Krysa, G.,Lewis, A.,Witherington, J.,Huet, P.,Dudit, Y.,Trottet, L.,Nicodeme, E. (deposition date: 2013-06-29, release date: 2013-09-11, Last modification date: 2024-05-08) |
| Primary citation | Mirguet, O.,Lamotte, Y.,Chung, C.,Bamborough, P.,Delannee, D.,Bouillot, A.,Gellibert, F.,Krysa, G.,Lewis, A.,Witherington, J.,Huet, P.,Dudit, Y.,Trottet, L.,Nicodeme, E. Naphthyridines as Novel Bet Family Bromodomain Inhibitors. Chemmedchem, 9:589-, 2014 Cited by PubMed Abstract: Bromodomains (BRDs) are small protein domains found in a variety of proteins that recognize and bind to acetylated histone tails. This binding affects chromatin structure and facilitates the localisation of transcriptional complexes to specific genes, thereby regulating epigenetically controlled processes including gene transcription and mRNA elongation. Inhibitors of the bromodomain and extra-terminal (BET) proteins BRD2-4 and T, which prevent bromodomain binding to acetyl-modified histone tails, have shown therapeutic promise in several diseases. We report here the discovery of 1,5-naphthyridine derivatives as potent inhibitors of the BET bromodomain family with good cell activity and oral pharmacokinetic parameters. X-ray crystal structures of naphthyridine isomers have been solved and quantum mechanical calculations have been used to explain the higher affinity of the 1,5-isomer over the others. The best compounds were progressed in a mouse model of inflammation and exhibited dose-dependent anti-inflammatory pharmacology. PubMed: 24000170DOI: 10.1002/CMDC.201300259 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.92 Å) |
Structure validation
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