6AFR

Crystal Structure of the first bromodomain of human BRD4 in complex with 5-((4-fluoro-1H-imidazol-1-yl)methyl)quinolin-8-ol

6AFR の概要

• エントリーDOI: 10.2210/pdb6afr/pdb
• 分子名称: Bromodomain-containing protein 4, 5-[(4-fluoranylimidazol-1-yl)methyl]quinolin-8-ol (3 entities in total)
• 機能のキーワード: brd4, epigenetic, signaling protein-inhibitor complex, signaling protein/inhibitor
• 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: 15342.62

構造登録者

Xing, J.,Zhang, R.K.,Zheng, M.Y.,Luo, C.,Jiang, X.R. (登録日: 2018-08-08, 公開日: 2018-12-12, 最終更新日: 2024-03-27)

主引用文献

Xing, J.,Zhang, R.,Jiang, X.,Hu, T.,Wang, X.,Qiao, G.,Wang, J.,Yang, F.,Luo, X.,Chen, K.,Shen, J.,Luo, C.,Jiang, H.,Zheng, M.
Rational design of 5-((1H-imidazol-1-yl)methyl)quinolin-8-ol derivatives as novel bromodomain-containing protein 4 inhibitors
Eur J Med Chem, 163:281-294, 2018

PubMed Abstract: Bromodomain-containing protein 4 (BRD4), an epigenetic reader of acetyl lysine, has emerged as a promising therapeutic target for many diseases including cancer, inflammation and heart failure. Our previous study reported that nitroxoline, an FDA approved antibiotic, showed potential BRD4 inhibitory activity and antiproliferation activity against leukemia cell lines. In this study, we further explored the structure-activity relationship (SAR) around nitroxoline and employed our previously developed machine learning based activity scoring function BRD4LGR for further analysis. To improve the cellular level activity, physico-chemical properties were optimized using computational approaches. Then the candidates were tested for their ADME/T profiles. Finally, based on this rational hit-to-lead optimization strategy, 3 drug-like BRD4 inhibitors were obtained, with different profiles on cell line selectivity for multiple myeloma, leukemia and triple negative breast cancer. Further mechanism study showed these compounds could down-regulate c-Myc to inhibit cancer cell growth. This work illustrates the application of multiple computer-aided drug design techniques in a hit-to-lead optimization scenario, and provides novel potent BRD4 inhibitors with different phenotype propensities for future cancer treatment.

PubMed: 30529546
DOI: 10.1016/j.ejmech.2018.11.018

実験手法

X-RAY DIFFRACTION (1.998 Å)