Enhancing the cellular anti-proliferation activity of pyridazinones as c-met inhibitors using docking analysis

doi:10.1016/j.ejmech.2015.03.041

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	Enhancing the cellular anti-proliferation activity of pyridazinones as c-met inhibitors using docking analysis
	Xing, Weiqiang 2; Ai, Jing3 ; Jin, Shiyu 2; Shi, Zhangxing 2; Peng, Xia 3; Wang, Lang 2; Ji, Yinchun 3; Lu, Dong 2; Liu, Yang 2; Geng, Meiyu3
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2015-05-05
卷号	95 页码:302-312
关键词	Pyridazinone c-Met inhibitor Anticancer Docking study
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2015.03.041
文献子类	Article
英文摘要	A series of 2, 6-disubstituted pyridazinone derivatives were evaluated and optimized for their c-Met inhibitory activity in enzyme and cellular assay. An analysis of the SAR results arising from computer modeling analysis of members of the library led to the proposal that in order to obtain optimal inhibitory activity in cellular systems the lipophilic/hydrophilic properties of individual structural fragments in the inhibitors need to match those of corresponding binding pockets in the enzyme. Guided by this proposal, the quinoline-pyridazinone 8a, containing hydrophobic 6-indolyl pyridazinone and quinoline moieties along with a hydrophilic morpholine terminal group, was designed and synthesized. The results of studies with this substance showed that it is a selective c-Met inhibitor with both a high enzyme inhibition IC50 value of 4.2 nM and a high EBC-1 cell proliferation inhibition 1050 value of 17 nM. (C) 2015 Elsevier Masson SAS. All rights reserved.
资助项目	National Natural Science Foundation of China[81202392] ; National Natural Science Foundation of China[81225022] ; National Natural Science Foundation of China[81102461] ; National S&T Major Projects[2012ZX09301001-007] ; SA-SIBS Scholarship Program[00000000]
WOS关键词	SELECTIVE KINASE INHIBITORS ; GROWTH-FACTOR RECEPTOR ; STRUCTURE-BASED DESIGN ; TARGET RESIDENCE TIME ; BIOLOGICAL EVALUATION ; DISCOVERY ; CANCER ; POTENT ; IDENTIFICATION ; OPTIMIZATION
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:000354139900026
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276537]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室药物化学研究室
通讯作者	Hu, Youhong
作者单位	1.Zhejiang Univ, Coll Pharmaceut Sci, Zhejiang Prov Key Lab Anticanc Drug Res, ZJU ENS Joint Lab Med Chem, Hangzhou 310058, Zhejiang, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Xing, Weiqiang,Ai, Jing,Jin, Shiyu,et al. Enhancing the cellular anti-proliferation activity of pyridazinones as c-met inhibitors using docking analysis[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2015,95:302-312.
APA	Xing, Weiqiang.,Ai, Jing.,Jin, Shiyu.,Shi, Zhangxing.,Peng, Xia.,...&Hu, Youhong.(2015).Enhancing the cellular anti-proliferation activity of pyridazinones as c-met inhibitors using docking analysis.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,95,302-312.
MLA	Xing, Weiqiang,et al."Enhancing the cellular anti-proliferation activity of pyridazinones as c-met inhibitors using docking analysis".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 95(2015):302-312.