Discovery, optimization and biological evaluation for novel c-Met kinase inhibitors

doi:10.1016/j.ejmech.2017.11.073

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物发现与设计中心

	Discovery, optimization and biological evaluation for novel c-Met kinase inhibitors
	Yuan, Haoliang 1,6; Liu, Qiufeng 2,3,4; Zhang, Li 1; Hu, Shihe 1; Chen, Tiantian 2; Li, Huifang 5; Chen, Yadong 1; Xu, Yechun2 ; Lu, Tao 1,6
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2018
卷号	143 页码:491-502
关键词	c-Met Virtual screening Pharmacophore X-ray crystallography Structural optimization
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2017.11.073
文献子类	Article
英文摘要	The c-Met kinase has emerged as an attractive target for developing antitumor agents because of its close relationship with the development of many human cancers, poor clinical outcomes and even drug resistance. A series of novel c-Met kinase inhibitors have been identified with multiple workflow in this work, including virtual screening, X-ray crystallography, biological evaluation and structural optimization. The experimentally determined crystal structure of the best hit compound HL-11 in c-Met kinase domain was highly consistent with the computational prediction. Comparison of the hit compounds with different c-Met kinase inhibitory activity by molecular dynamics simulations suggested the key protein-ligand interactions for structural optimization. Based on these, structural optimization produced compound 11e with better c-Met kinase inhibitory activity and improved anti-proliferative activity. These experimental findings proved the reliability and efficiency of our in silico methods. This strategy will facilitate further lead discovery and optimization for novel c-Met kinase inhibitors. (C) 2017 Elsevier Masson SAS. All rights reserved.
资助项目	National Science Foundation of China[81422047] ; National Science Foundation of China[81473078] ; National Science Foundation of China[81703367] ; scientific research funds for new teacher of China Pharmaceutical University[3014070086] ; Fundamental Research Funds for the Central Universities[2632017PY12] ; "111 Project" from the Ministry of Education of China, the State Administration of Foreign Expert Affairs of China[111-2-07]
WOS关键词	CANCER ; EXPRESSION ; MUTATIONS ; RECEPTOR ; PROGRESS
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000428216700040
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272322]
专题	药物发现与设计中心
通讯作者	Xu, Yechun; Lu, Tao
作者单位	1.China Pharmaceut Univ, Sch Sci, Lab Mol Design & Drug Discovery, 24 Tongjiaxiang, Nanjing 210009, Jiangsu, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Key Lab Receptor Res, Shanghai 201203, Peoples R China; 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China; 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 5.Univ British Columbia, Vancouver Prostate Ctr, 2660 Oak St, Vancouver, BC V6H 3Z6, Canada 6.China Pharmaceut Univ, Inst Pharmaceut Res, Jiangsu Key Lab Drug Discovery Metab Dis, State Key Lab Nat Med, 24 Tongjiaxiang, Nanjing 210009, Jiangsu, Peoples R China;
推荐引用方式 GB/T 7714	Yuan, Haoliang,Liu, Qiufeng,Zhang, Li,et al. Discovery, optimization and biological evaluation for novel c-Met kinase inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2018,143:491-502.
APA	Yuan, Haoliang.,Liu, Qiufeng.,Zhang, Li.,Hu, Shihe.,Chen, Tiantian.,...&Lu, Tao.(2018).Discovery, optimization and biological evaluation for novel c-Met kinase inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,143,491-502.
MLA	Yuan, Haoliang,et al."Discovery, optimization and biological evaluation for novel c-Met kinase inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 143(2018):491-502.