Rational design of 5-((1H-imidazol-1-yl)methyl)quinolin-8-ol derivatives as novel bromodomain-containing protein 4 inhibitors

doi:10.1016/j.ejmech.2018.11.018

	Rational design of 5-((1H-imidazol-1-yl)methyl)quinolin-8-ol derivatives as novel bromodomain-containing protein 4 inhibitors
	Xing, Jing 2,3; Zhang, Rukang 2,3; Jiang, Xiangrui4,5 ; Hu, Tianwen 2; Wang, Xinjun 6; Qiao, Gang 6; Wang, Junjian 7; Yang, Fengling 7,8; Luo, Xiaomin2 ; Chen, Kaixian2,9
刊名	European journal of medicinal chemistry
	2018-11-16
卷号	163 页码:281-294
ISSN号	1768-3254
DOI	10.1016/j.ejmech.2018.11.018
文献子类	Article
英文摘要	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.
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/266332]
专题	药物化学研究室药物发现与设计中心
通讯作者	Shen, Jingshan; Luo, Cheng; Zheng, Mingyue
作者单位	1.CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China 2.Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; 3.University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China; 4.Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; 5.CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; 6.Suplead Co., LTD, Building D, 389 Ruoshui Road, Suzhou, 215000, China; 7.College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, 450001, China; 8.College of Life Science and Engineering, Henan University of Urban Construction, Pingdingshan, 467036, China; 9.School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China;
推荐引用方式 GB/T 7714	Xing, Jing,Zhang, Rukang,Jiang, Xiangrui,et al. Rational design of 5-((1H-imidazol-1-yl)methyl)quinolin-8-ol derivatives as novel bromodomain-containing protein 4 inhibitors[J]. European journal of medicinal chemistry,2018,163:281-294.
APA	Xing, Jing.,Zhang, Rukang.,Jiang, Xiangrui.,Hu, Tianwen.,Wang, Xinjun.,...&Zheng, Mingyue.(2018).Rational design of 5-((1H-imidazol-1-yl)methyl)quinolin-8-ol derivatives as novel bromodomain-containing protein 4 inhibitors.European journal of medicinal chemistry,163,281-294.
MLA	Xing, Jing,et al."Rational design of 5-((1H-imidazol-1-yl)methyl)quinolin-8-ol derivatives as novel bromodomain-containing protein 4 inhibitors".European journal of medicinal chemistry 163(2018):281-294.