7V1U

Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor ZJ12

Summary for 7V1U

• Entry DOI: 10.2210/pdb7v1u/pdb
• Descriptor: Bromodomain-containing protein 4, ~{N}-(3-ethyl-6-methoxy-1,2-benzoxazol-5-yl)-2-methoxy-benzenesulfonamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: brd4(1), bromodomain, protein binding
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 17191.79

Authors

Zhang, M.,Wang, C.,Zhang, C.,Zhang, Y.,Xu, Y. (deposition date: 2021-08-06, release date: 2022-08-10, Last modification date: 2023-11-29)

Primary citation

Zhang, M.F.,Luo, X.Y.,Zhang, C.,Wang, C.,Wu, X.S.,Xiang, Q.P.,Xu, Y.,Zhang, Y.
Design, synthesis and pharmacological characterization of N-(3-ethylbenzo[d]isoxazol-5-yl) sulfonamide derivatives as BRD4 inhibitors against acute myeloid leukemia.
Acta Pharmacol.Sin., 43:2735-2748, 2022

PubMed Abstract: BRD4 plays a key role in the regulation of gene transcription and has been identified as an attractive target for cancer treatment. In this study, we designed 26 new compounds by modifying 3-ethyl-benzo[d]isoxazole core with sulfonamides. Most compounds exhibited potent BRD4 binding activities with ΔT values exceeding 6 °C. Two crystal structures of 11h and 11r in complex with BRD4(1) were obtained to characterize the binding patterns. Compounds 11h and 11r were effective for BRD4(1) binding and showed remarkable anti-proliferative activity against MV4-11 cells with IC values of 0.78 and 0.87 μM. Furthermore, 11r (0.5-10 μM) concentration-dependently inhibited the expression levels of oncogenes including c-Myc and CDK6 in MV4-11 cells. Moreover, 11r (0.5-10 μM) concentration-dependently blocked cell cycle in MV4-11 cells at G/G phase and induced cell apoptosis. Compound 11r may serve as a new lead compound for further drug development.

PubMed: 35264812
DOI: 10.1038/s41401-022-00881-y

Experimental method

X-RAY DIFFRACTION (1.82 Å)