8WQO

Crystal structure of BRD4-BD1 bound with DI106

8WQO の概要

• エントリーDOI: 10.2210/pdb8wqo/pdb
• 分子名称: 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)
• 機能のキーワード: inhibitor, transcription
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 15145.55

構造登録者

Cao, D.,Xiong, B. (登録日: 2023-10-12, 公開日: 2024-07-24, 最終更新日: 2025-02-19)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.13 Å)