Simm530, a novel and highly selective c-Met inhibitor, blocks c-Met-stimulated signaling and neoplastic activities

doi:10.18632/oncotarget.9349

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	Simm530, a novel and highly selective c-Met inhibitor, blocks c-Met-stimulated signaling and neoplastic activities
	Wang, Ying 2; Zhan, Zhengsheng 3; Jiang, Xifei 1,4; Peng, Xia 2; Shen, Yanyan 2; Chen, Fang 3; Ji, Yinchun 2; Liu, Weiren 1,4; Shi, Yinghong 1,4; Duan, Wenhu3
刊名	ONCOTARGET
	2016-06-21
卷号	7 期号:25 页码:38091-38104
关键词	c-Met kinase inhibitor Simm530
ISSN号	1949-2553
DOI	10.18632/oncotarget.9349
文献子类	Article
英文摘要	The aberrant c-Met activation has been implicated in a variety of human cancers for its critical role in tumor growth, metastasis and tumor angiogenesis. Thus, c-Met axis presents as an attractive therapeutic target. Notably, most of these c-Met inhibitors currently being evaluated in clinical trials lack selectivity and target multiple kinases, often accounting for the undesirable toxicities. Here we described Simm530 as a potent and selective c-Met inhibitor. Simm530 demonstrated >2,000 fold selectivity for c-Met compared with other 282 kinases, making it one of the most selective c-Met inhibitors described to date. This inhibitor significantly blocked c-Met signaling pathways regardless of mechanistic complexity implicated in c-Met activation. As a result, Simm530 led to substantial inhibition of c-Met-promoted cell proliferation, migration, invasion, ECM degradation, cell scattering and invasive growth. In addition, Simm530 inhibited primary human umbilical vascular endothelial cell (HUVEC) proliferation, decreased intratumoral CD31 expression and plasma pro-angiogenic factor interleukin-8 secretion, suggesting its significant anti-angiogenic properties. Simm530 resulted in dose-dependent inhibition of c-Met phosphorylation and tumor growth in c-Met-driven lung and gastric cancer xenografts. And, the inhibitor is well tolerated even at doses that achieve complete tumor regression. Together, Simm530 is a potent and highly selective c-Met kinase inhibitor that may have promising therapeutic potential in c-Met-driven cancer treatment.
资助项目	National Program on Key Basic Research Project of China[2012CB910704] ; National Key Sci-Tech Project[2012ZX09301001-007] ; Natural Science Foundation of China[81321092] ; Natural Science Foundation of China[81473243]
WOS关键词	HEPATOCYTE GROWTH-FACTOR ; SMALL-MOLECULE INHIBITOR ; SCATTER-FACTOR ; KINASE INHIBITOR ; TYROSINE KINASE ; ACQUIRED-RESISTANCE ; ONCOGENE ADDICTION ; INVASIVE GROWTH ; GASTRIC-CANCER ; RECEPTOR
WOS研究方向	Oncology ; Cell Biology
语种	英语
出版者	IMPACT JOURNALS LLC
WOS记录号	WOS:000378229100054
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275990]
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	Ai, Jing; Geng, Meiyu
作者单位	1.Fudan Univ, Dept Liver Surg, Liver Canc Inst, Zhongshan Hosp, Shanghai 200433, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 200031, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 200031, Peoples R China; 4.Minist Educ, Key Lab Carcinogenesis & Canc Invas, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Wang, Ying,Zhan, Zhengsheng,Jiang, Xifei,et al. Simm530, a novel and highly selective c-Met inhibitor, blocks c-Met-stimulated signaling and neoplastic activities[J]. ONCOTARGET,2016,7(25):38091-38104.
APA	Wang, Ying.,Zhan, Zhengsheng.,Jiang, Xifei.,Peng, Xia.,Shen, Yanyan.,...&Geng, Meiyu.(2016).Simm530, a novel and highly selective c-Met inhibitor, blocks c-Met-stimulated signaling and neoplastic activities.ONCOTARGET,7(25),38091-38104.
MLA	Wang, Ying,et al."Simm530, a novel and highly selective c-Met inhibitor, blocks c-Met-stimulated signaling and neoplastic activities".ONCOTARGET 7.25(2016):38091-38104.