Yhhu3813 is a novel selective inhibitor of c-Met kinase that inhibits c-Met-dependent neoplastic phenotypes of human cancer cells

doi:10.1038/aps.2013.125

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	Yhhu3813 is a novel selective inhibitor of c-Met kinase that inhibits c-Met-dependent neoplastic phenotypes of human cancer cells
	He, Chang-xi 1; Ai, Jing1 ; Xing, Wei-qiang 2; Chen, Yi1 ; Zhang, Hao-tian 1; Huang, Min1 ; Hu, You-hong2 ; Ding, Jian1 ; Geng, Mei-yu1
刊名	ACTA PHARMACOLOGICA SINICA
	2014-01
卷号	35 期号:1 页码:89-97
关键词	human cancer anticancer drug Yhhu3813 c-Met receptor tyrosine kinase xenograft nude mouse model
ISSN号	1671-4083
DOI	10.1038/aps.2013.125
文献子类	Article
英文摘要	Aim: c-Met kinase deregulation is strongly associated with the formation, progression and dissemination of human cancers. In this study we identified Yhhu3813 as a small-molecule inhibitor of c-Met kinase and characterized its antitumor properties both in vitro and in vivo. Methods: The activities of different kinases were measured using ELISA assays and signaling proteins in the cells were detected with Western blotting. Cell proliferation was assessed using SRB or MTT assay in twenty human cell lines and cell cycle distribution was determined with flow cytometry. Transwell-based assay was used to evaluate cell migration and invasion. Cell invasive growth was detected by a morphogenesis assay. c-Met overactivated human NSCLC cell line EBC-1 xenografts were used to evaluate the in vivo anti-tumor efficacy. Results: Yhhu3813 potently inhibited c-Met kinase activity in vitro with an IC50 value of 2.4 +/- 0.3 nmol/L, > 400-fold higher than that for a panel of 15 different tyrosine kinases, suggesting a high selectivity of Yhhu3813. The compound (20, 100 and 500 nmol/L) dose-dependently inhibited the phosphorylation of c-Met and its key downstream Akt and Erk signal cascades in multiple c-Met aberrant human cancer cell lines, regardless of the mechanistic complexity in c-Met activation across different cellular contexts. In 20 human cancer cell lines harboring different backgrounds of c-Met expression/activation, Yhhu3813 potently inhibited c-Met-driven cell proliferation via arresting cells at G(1)/S phase. Furthermore, Yhhu3813 substantially impaired c-Met-mediated cell migration, invasion, scattering, and invasive growth. Oral administration of EBC-1 xenograft mice with Yhhu3813 (50 or 100 mg.kg(-1).d(-1), qd, for 2 weeks) dose-dependently suppressed the tumor growth, which was correlated with a reduction in the intratumoral proliferation index and c-Met signaling. Conclusion: Yhhu3813 is a potent selective inhibitor of c-Met that inhibits c-Met-dependent neoplastic phenotypes of human cancer cells in vitro and in vivo.
资助项目	National Program on Key Basic Research Project of China[2012CB910704] ; Natural Science Foundation of China for Innovation Research Group[81021062] ; National Natural Science Foundation of China[81102461] ; National S&T Major Projects[2012ZX09301001-007]
WOS关键词	HEPATOCYTE GROWTH-FACTOR ; EPITHELIAL-MESENCHYMAL TRANSITION ; RECEPTOR TYROSINE KINASES ; FACTOR/SCATTER FACTOR ; TUMOR PROGRESSION ; PROSTATE-CANCER ; INVASIVE GROWTH ; LUNG-CANCER ; HGF ; PROTOONCOGENE
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:5040815
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000330581000011
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277317]
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
通讯作者	Geng, Mei-yu
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	He, Chang-xi,Ai, Jing,Xing, Wei-qiang,et al. Yhhu3813 is a novel selective inhibitor of c-Met kinase that inhibits c-Met-dependent neoplastic phenotypes of human cancer cells[J]. ACTA PHARMACOLOGICA SINICA,2014,35(1):89-97.
APA	He, Chang-xi.,Ai, Jing.,Xing, Wei-qiang.,Chen, Yi.,Zhang, Hao-tian.,...&Geng, Mei-yu.(2014).Yhhu3813 is a novel selective inhibitor of c-Met kinase that inhibits c-Met-dependent neoplastic phenotypes of human cancer cells.ACTA PHARMACOLOGICA SINICA,35(1),89-97.
MLA	He, Chang-xi,et al."Yhhu3813 is a novel selective inhibitor of c-Met kinase that inhibits c-Met-dependent neoplastic phenotypes of human cancer cells".ACTA PHARMACOLOGICA SINICA 35.1(2014):89-97.