21OJ
Crystal Structure of the second bromodomain of human BRD4 BD2 in complex with the covalent inhibitor
This is a non-PDB format compatible entry.
Summary for 21OJ
| Entry DOI | 10.2210/pdb21oj/pdb |
| Descriptor | Bromodomain-containing protein 4, 4-[2-[2,6-dimethyl-4-[(2~{S})-2-methyl-3-oxidanyl-propoxy]phenoxy]-5-(2-oxidanylpropan-2-yl)phenyl]-6-methyl-7-oxidanylidene-~{N}-prop-2-ynyl-1~{H}-pyrrolo[2,3-c]pyridine-2-carboxamide, GLYCEROL, ... (4 entities in total) |
| Functional Keywords | chromatin reader protein, covalent inhibitor, complex, protein binding |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 27624.01 |
| Authors | |
| Primary citation | Kang, J.,Wang, X.,Zhang, H.,Lin, J.,Chen, P.,Wang, Z.,Hao, Z.,Miao, F.,Zhang, F.,Li, T.,Xie, Y.,Wang, J.,Zhang, Z.M.,Yao, S.Q.,Lu, X. Dual-Site Covalent Targeting Enables BD2-Selective BET Inhibition With Potent Antitumor Activity in Mice. Angew.Chem.Int.Ed.Engl., 65:e1224416-e1224416, 2026 Cited by PubMed Abstract: Bromodomain and extra-terminal (BET) proteins are validated therapeutic targets for cancer, but clinical translation of pan-BET inhibitors is limited by dose-limiting toxicities from non-selective inhibition of BD1/BD2 domains. Herein, we report the first-ever domain-selective covalent inhibitor, named ipAE1, of BET BD2 domains by installing an epoxide warhead onto the scaffold of ABBV-744. ipAE1 was shown to irreversibly modify Glu438 and His437 (to a lesser extent) located within the BRD4(2) binding pocket via a dual-covalent mechanism, as evidenced by its chemical probe pAE1. Furthermore, ipAE1 exhibited exceptional potency against BRD4(2) (K = 0.096 nM) with > 1900-fold selectivity over BRD4(1), leading to potent and sustained antiproliferative activity in MV4-11 cells (GI = 1.5 nM). Subsequent live-cell proteome-wide profiling validated BRD4 as the primary cellular target of ipAE1. Consistent with cellular activities, ipAE1 possessed a significantly enhanced antitumor efficacy in an MV4-11 xenografted mouse model compared to ABBV-744, presumably due to its on-target covalent engagement in vivo. Our study thus establishes for the first time a novel targeted covalent inhibition (TCI) strategy that engages two weakly nucleophilic residues within a single bromodomain, an approach generalizable to other compounds targeting E/H, providing a highly selective platform for future development of next-generation BET inhibitors. PubMed: 42695248DOI: 10.1002/anie.1224416 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.60014166736 Å) |
Structure validation
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