5H21

Trimethoxy-ring inhibitor in complex with the first bromodomain of BRD4

Summary for 5H21

• Entry DOI: 10.2210/pdb5h21/pdb
• Descriptor: Bromodomain-containing protein 4, 3,4,5-trimethoxy-~{N}-(2-thiophen-2-ylethyl)benzamide (3 entities in total)
• Functional Keywords: brd4, inhibitor, peptide binding protein-inhibitor complex, peptide binding protein/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 17016.56

Authors

Zhang, H.,Luo, C. (deposition date: 2016-10-13, release date: 2017-07-05, Last modification date: 2024-03-20)

Primary citation

Chen, Z.,Zhang, H.,Liu, S.,Xie, Y.,Jiang, H.,Lu, W.,Xu, H.,Yue, L.,Zhang, Y.,Ding, H.,Zheng, M.,Yu, K.,Chen, K.,Jiang, H.,Luo, C.
Discovery of novel trimethoxy-ring BRD4 bromodomain inhibitors: AlphaScreen assay, crystallography and cell-based assay.
Medchemcomm, 8:1322-1331, 2017

PubMed Abstract: As a member of the bromodomain and extra terminal domain (BET) protein family, BRD4 is closely related to cancers and other diseases. Small-molecule BRD4 inhibitors have already demonstrated promising potential for the therapy of BRD4-related cancers. In this study, we report the discovery and evaluation of a novel category of BRD4 inhibitors, which share a trimethoxy ring and target the first bromodomain of the human BRD4 protein. The IC value of the most potent compound, DC-BD-03, is 2.01 μM. In addition, a high-resolution crystal structure of the compound DC-BD-29 with the first bromodomain of BRD4 was determined, which revealed the binding mode and facilitated further structure-based optimization. These compounds exhibited anti-proliferation activity, caused cell cycle arrest, and induced apoptosis in human leukemia MV4-11 cells. Thus, the results presented in this study indicated the potential of this series of compounds as drug candidates for the therapy of BRD4-related cancers.

PubMed: 30108844
DOI: 10.1039/c7md00083a

Experimental method

X-RAY DIFFRACTION (1.591 Å)