8WQO

Crystal structure of BRD4-BD1 bound with DI106

Summary for 8WQO

• Entry DOI: 10.2210/pdb8wqo/pdb
• Descriptor: Isoform C of Bromodomain-containing protein 4, (3~{R})-6-[[4-(3,5-dimethyl-1~{H}-pyrazol-4-yl)pyrimidin-2-yl]amino]-1,3-dimethyl-4-propan-2-yl-3~{H}-quinoxalin-2-one (3 entities in total)
• Functional Keywords: inhibitor, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 15145.55

Authors

Cao, D.,Xiong, B. (deposition date: 2023-10-12, release date: 2024-07-24, Last modification date: 2025-02-19)

Primary citation

Lyu, K.,Ren, Y.,Mou, J.,Yang, Y.,Pan, Y.,Zhang, H.,Li, Y.,Cao, D.,Chen, L.,Chen, D.,Guo, D.,Xiong, B.
Structure-Based Rational Design and Evaluation of BET-Aurora Kinase Dual-Inhibitors for Treatment of Cancers.
J.Med.Chem., 68:1344-1364, 2025

PubMed Abstract: Simultaneous inhibition of the bromodomain and extra-terminal domain and Aurora kinases is a promising anticancer therapeutic strategy. Based on our previous study on BET-kinase dual inhibitors, we employed the molecular docking approach to design novel dual BET-Aurora kinase A inhibitors. Through several rounds of optimization and with the guidance of the solved cocrystal structure of BRD4 bound to inhibitor , we finally obtained a series of highly potent dual BET-Aurora kinase A inhibitors. Compound exhibited strong affinity toward both BRD4 and Aurora kinase A. It also showed good antiproliferative activities on diverse cancer cell lines, good pharmacokinetic profiles, and favorable antitumor efficacy in renal cell cancer and colon cancer xenograft models with TGI of 45.99% and 53.06%, respectively. The development of compound reinforces the concept that a rational design may achieve dual inhibitors targeting specific kinases and bromodomain proteins.

PubMed: 39844725
DOI: 10.1021/acs.jmedchem.4c01933

Experimental method

X-RAY DIFFRACTION (1.13 Å)