4A9O
N-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH 5 ethyl-3-methyl-4-phenyl-1, 2-oxazole
Summary for 4A9O
| Entry DOI | 10.2210/pdb4a9o/pdb |
| Related | 1X0J 2YDW 2YEK 4A9E 4A9F 4A9H 4A9I 4A9J 4A9M |
| Descriptor | BROMODOMAIN CONTAINING 2, 1,2-ETHANEDIOL, 5-ETHYL-3-METHYL-4-PHENYL-1,2-OXAZOLE, ... (5 entities in total) |
| Functional Keywords | signaling protein-inhibitor complex, signaling protein/inhibitor |
| Biological source | HOMO SAPIENS (HUMAN) |
| Cellular location | Nucleus (By similarity): P25440 |
| Total number of polymer chains | 3 |
| Total formula weight | 54700.22 |
| Authors | Chung, C.W.,Bamborough, P. (deposition date: 2011-11-26, release date: 2012-02-08, Last modification date: 2024-05-08) |
| Primary citation | Bamborough, P.,Diallo, H.,Goodacre, J.D.,Gordon, L.,Lewis, A.,Seal, J.T.,Wilson, D.M.,Woodrow, M.D.,Chung, C.W. Fragment-Based Discovery of Bromodomain Inhibitors Part 2: Optimization of Phenylisoxazole Sulfonamides. J.Med.Chem., 55:587-, 2012 Cited by PubMed Abstract: Bromodomains are epigenetic reader modules that regulate gene transcription through their recognition of acetyl-lysine modified histone tails. Inhibitors of this protein-protein interaction have the potential to modulate multiple diseases as demonstrated by the profound anti-inflammatory and antiproliferative effects of a recently disclosed class of BET compounds. While these compounds were discovered using phenotypic assays, here we present a highly efficient alternative approach to find new chemical templates, exploiting the abundant structural knowledge that exists for this target class. A phenyl dimethyl isoxazole chemotype resulting from a focused fragment screen has been rapidly optimized through structure-based design, leading to a sulfonamide series showing anti-inflammatory activity in cellular assays. This proof-of-principle experiment demonstrates the tractability of the BET family and bromodomain target class to fragment-based hit discovery and structure-based lead optimization. PubMed: 22136469DOI: 10.1021/JM201283Q PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.78 Å) |
Structure validation
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