8WY3
Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor 21
Summary for 8WY3
| Entry DOI | 10.2210/pdb8wy3/pdb |
| Descriptor | Bromodomain-containing protein 4, ~{N}-cyclopropyl-2-[[5-[2-(4-fluoranyl-2,6-dimethyl-phenoxy)-5-(2-oxidanylpropan-2-yl)phenyl]-1-methyl-2-oxidanylidene-pyridin-4-yl]amino]ethanamide (3 entities in total) |
| Functional Keywords | brd4(1), bromodomain, protein binding |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 3 |
| Total formula weight | 51782.69 |
| Authors | |
| Primary citation | Jiang, W.,Hou, Q.,Xu, H.,Yang, K.,Wang, X.,Zhang, K.,Zeng, Y.,Li, W.,Wang, B.,Luo, G.,Zhao, X.,Shen, H.,Xu, Y.,Wu, X. Discovery of Novel Phenoxyaryl Pyridones as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with High Selectivity for the Second Bromodomain (BD2) to Potentially Treat Acute Myeloid Leukemia. J.Med.Chem., 67:1513-1532, 2024 Cited by PubMed Abstract: Bromodomain-selective BET inhibition has emerged as a promising strategy to improve the safety profiles of -BET inhibitors. Herein, we report the discovery of potent phenoxyaryl pyridones as highly BD2-selective BET inhibitors. Compound (IC = 2.9 nM) exhibited a comparable BRD4 BD2 inhibitory activity relative to (IC = 1.0 nM) and remarkably improved selectivity over BRD4 BD1 (: 2583-fold; : 344-fold). This lead compound significantly inhibited the proliferation of acute myeloid leukemia (AML) cell lines through induction of G0/G1 arrest and apoptosis . Excellent antitumor efficacy with was achieved in an MV;411 mouse xenograft model. Pleasingly, compound (hERG IC > 30 μM) mitigated the inhibition of the human ether-à-go-go-related gene (hERG) ion channel compared with (hERG IC = 2.8 μM). This work provides a promising BD2-selective lead for the development of more effective and safe BET inhibitors as anticancer agents. PubMed: 38175809DOI: 10.1021/acs.jmedchem.3c02104 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.78 Å) |
Structure validation
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