5WUU

Complex structure of the first bromodomain of BRD4 with an inhibitor that containing a 2H-chromen-2-one ring

Summary for 5WUU

• Entry DOI: 10.2210/pdb5wuu/pdb
• Descriptor: Bromodomain-containing protein 4, ~{N}-methyl-~{N}-[3-[(2-oxidanylidenechromen-4-yl)amino]propyl]thiophene-2-carboxamide (3 entities in total)
• Functional Keywords: brd4, inhibitor, complex, transcription
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: O60885
• Total number of polymer chains: 1
• Total formula weight: 17037.59

Authors

Zhang, H.,Sun, Z.Y. (deposition date: 2016-12-21, release date: 2017-04-12, Last modification date: 2023-11-22)

Primary citation

Sun, Z.,Zhang, H.,Chen, Z.,Xie, Y.,Jiang, H.,Chen, L.,Ding, H.,Zhang, Y.,Jiang, H.,Zheng, M.,Luo, C.
Discovery of novel BRD4 inhibitors by high-throughput screening, crystallography, and cell-based assays.
Bioorg. Med. Chem. Lett., 27:2003-2009, 2017

PubMed Abstract: As an epigenetic reader, BRD4 regulates the transcription of important downstream genes that are essential for the survival of tumor cells. Small molecular inhibitors targeting the first bromodomain of BRD4 (BRD4-BD1) have showed promising potentials in the therapies of BRD4-related cancers. Through AlphaScreen-based high-throughput screening assay, a novel small molecular inhibitor was identified, and named DCBD-005, which inhibited the binding between BRD4-BD1 and acetylated lysines with an IC value of 0.81±0.03μM. The compound DCBD-005 effectively inhibited the viability, caused cell cycle arrest, and induced apoptosis in human leukemia MV4-11 cells. Moreover, the crystal structure of compound DCBD-005 with the BRD4-BD1 was determined at 1.72Å resolution, which revealed the binding mechanism of the leading compound, and also provided solid basis for further structure-based optimization. These results indicated that this novel BRD4-BD1 inhibitor DCBD-005 is promising to be developed into a drug candidate in the treatment of BRD4-related diseases.

PubMed: 28347667
DOI: 10.1016/j.bmcl.2017.03.012

Experimental method

X-RAY DIFFRACTION (1.724 Å)