yhhu3813isanovelselectiveinhibitorofcmetkinasethatinhibitscmetdependentneoplasticphenotypesofhumancancercells

	yhhu3813isanovelselectiveinhibitorofcmetkinasethatinhibitscmetdependentneoplasticphenotypesofhumancancercells
	He Changxi 1; Ai Jing 1; Xing Weiqiang 2; Chen Yi 1; Zhang Haotian 1; Huang Min 1; Hu Youhong 2; Ding Jian 1; Geng Meiyu 1
刊名	actapharmacologicasinica
	2014
卷号	000 期号:001 页码:89
关键词	选择性抑制剂抗肿瘤特性激酶活性癌细胞依赖性人类表型 Western印迹
ISSN号	1671-4083
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 G1/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.
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/288180]
专题	中国科学院上海药物研究所
作者单位	1.中国科学院 2.中国科学院上海药物研究所
推荐引用方式 GB/T 7714	He Changxi,Ai Jing,Xing Weiqiang,et al. yhhu3813isanovelselectiveinhibitorofcmetkinasethatinhibitscmetdependentneoplasticphenotypesofhumancancercells[J]. actapharmacologicasinica,2014,000(001):89.
APA	He Changxi.,Ai Jing.,Xing Weiqiang.,Chen Yi.,Zhang Haotian.,...&Geng Meiyu.(2014).yhhu3813isanovelselectiveinhibitorofcmetkinasethatinhibitscmetdependentneoplasticphenotypesofhumancancercells.actapharmacologicasinica,000(001),89.
MLA	He Changxi,et al."yhhu3813isanovelselectiveinhibitorofcmetkinasethatinhibitscmetdependentneoplasticphenotypesofhumancancercells".actapharmacologicasinica 000.001(2014):89.