7C6P

Bromodomain-containing 4 BD2 in complex with 3',4',7,8- Tetrahydroxyflavonoid

Summary for 7C6P

• Entry DOI: 10.2210/pdb7c6p/pdb
• Related: 7C2Z
• Descriptor: Bromodomain-containing protein 4, 2-[3,4-bis(oxidanyl)phenyl]-7,8-bis(oxidanyl)chromen-4-one (3 entities in total)
• Functional Keywords: brd4, bd2, 3', 4', 7, 8- tetrahydroxyflavonoid, acute myeloid leukemia, c-myc, gene regulation
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 13093.17

Authors

Li, J.,Yu, K.,Luo, Y.,Zheng, W.,Liang, W.,Zhu, J. (deposition date: 2020-05-22, release date: 2021-05-12, Last modification date: 2025-03-12)

Primary citation

Li, J.,Zou, W.,Yu, K.,Liu, B.,Liang, W.,Wang, L.,Lu, Y.,Jiang, Z.,Wang, A.,Zhu, J.
Discovery of the natural product 3',4',7,8-tetrahydroxyflavone as a novel and potent selective BRD4 bromodomain 2 inhibitor.
J Enzyme Inhib Med Chem, 36:903-913, 2021

PubMed Abstract: Bromodomain-containing protein 4 (BRD4) binds acetylated lysine residues on the N-terminal tails of histones through two bromodomains (BD1 and BD2) to regulate gene transcription. Inhibiting one or both of bromodomains resulted in different phenotypes, suggesting BD1 and BD2 may have different functions. Here we report the characterisation of a natural product 3',4',7,8-tetrahydroxyflavone as a novel and potent selective BRD4 inhibitor. The compound is 100-fold more selective for BRD4-BD2 (IC50 = 204 nM) than BRD4-BD1 (IC=17.9 µM). Co-crystal structures show 3',4',7,8-tetrahydroxyflavone binds to the acetylated lysine binding pocket of BRD4-BD1 or BRD4-BD2, but establishes more interactions with BRD4-BD2 than BRD4-BD1. Our data suggest 3',4',7,8-tetrahydroxyflavone as a potent selective inhibitor of BRD4-BD2 with a novel chemical scaffold. Given its distinct chemical structure from current BRD4 inhibitors, this compound may open the door for a novel class of anti-BRD4 inhibitors by serving as a lead compound.

PubMed: 33820450
DOI: 10.1080/14756366.2021.1906663

Experimental method

X-RAY DIFFRACTION (1.73 Å)