SOMG-833, a Novel Selective c-MET Inhibitor, Blocks c-MET-Dependent Neoplastic Effects and Exerts Antitumor Activity

doi:10.1124/jpet.114.214817

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

	SOMG-833, a Novel Selective c-MET Inhibitor, Blocks c-MET-Dependent Neoplastic Effects and Exerts Antitumor Activity
	Zhang, Hao-tian 1; Wang, Lu 2; Ai, Jing2 ; Chen, Yi2 ; He, Chang-xi 2; Ji, Yin-chun 2; Huang, Min2 ; Yang, Jing-yu 1; Zhang, Ao3,4 ; Ding, Jian2
刊名	JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
	2014-07
卷号	350 期号:1 页码:36-45
ISSN号	0022-3565
DOI	10.1124/jpet.114.214817
文献子类	Article
英文摘要	The hepatocyte growth factor/c-MET signaling axis plays an important role in tumor cell proliferation, metastasis, and tumor angiogenesis, and therefore presents as an attractive target for cancer therapy. Notably, most small-molecule c-MET inhibitors currently undergoing clinical trials are multitarget inhibitors with the unwanted inhibition of additional kinases, often accounting for undesirable toxicity. Here, we discovered SOMG-833 [3-(4-methylpiperazin-1-yl)-5-(3-nitrobenzylamino)-7( trifluoromethyl) quinoline] as a potent and selective smallmolecule c-MET inhibitor, with an average IC50 of 0.93 nM against c-MET, over 10,000-fold more potent compared with 19 tyrosine kinases, including c-MET family members and highly homologous kinases. SOMG-833 strongly suppressed c-MET-mediated signaling transduction regardless of mechanistic complexity implicated in c-MET activation, including MET gene amplification, MET gene fusion, and HGF-stimulated c-MET activation. In a panel of 24 human cancer or genetically engineered model cell lines, SOMG-833 potently inhibited c-MET-driven cell proliferation, whereas cancer cells lacking c-MET activation were markedly less sensitive (at least 15-fold) to the treatment. SOMG-833 also suppressed c-MET-mediated migration, invasion, urokinase activity, and invasive growth phenotype. In addition, inhibition of primary human umbilical vascular endothelial cell (HUVEC) proliferation and downregulation of plasma proangiogenic factor interleukin-8 secretion resulted from SOMG-833 treatment, suggesting its significant antiangiogenic properties. Together, these results led to the remarkable antitumor efficacy of SOMG-833 in vivo, as demonstrated in c-MET-dependent NIH-3T3/TPR-MET, U-87MG, and EBC-1 xenograft models. Collectively, our results suggested SOMG-833 as a promising candidate for highly selective c-MET inhibition and a powerful tool to investigate the sole role of MET kinase in cancer.
资助项目	National Program on Key Basic Research Project of China[2012CB910704] ; National Natural Science Foundation[91229205] ; National Natural Science Foundation[81102461] ; National S&T Major Projects[2012ZX09301001-007] ; China Marine Commonwealth Research Project[201005022-5]
WOS关键词	HEPATOCYTE GROWTH-FACTOR ; RECEPTOR TYROSINE KINASE ; SCATTER-FACTOR ; INVASIVE GROWTH ; LUNG-CANCER ; PHASE-II ; ANGIOGENESIS ; METASTASIS ; RESISTANCE ; CELLS
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS记录号	WOS:000339270200005
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277003]
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	Yang, Jing-yu
作者单位	1.Shenyang Pharmaceut Univ, Dept Pharmacol, Shenyang 110016, 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, CAS Key Lab Receptor Res, Shanghai 200031, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, Synthet Organ & Med Chem Lab, Shanghai 200031, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Hao-tian,Wang, Lu,Ai, Jing,et al. SOMG-833, a Novel Selective c-MET Inhibitor, Blocks c-MET-Dependent Neoplastic Effects and Exerts Antitumor Activity[J]. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,2014,350(1):36-45.
APA	Zhang, Hao-tian.,Wang, Lu.,Ai, Jing.,Chen, Yi.,He, Chang-xi.,...&Geng, Mei-yu.(2014).SOMG-833, a Novel Selective c-MET Inhibitor, Blocks c-MET-Dependent Neoplastic Effects and Exerts Antitumor Activity.JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,350(1),36-45.
MLA	Zhang, Hao-tian,et al."SOMG-833, a Novel Selective c-MET Inhibitor, Blocks c-MET-Dependent Neoplastic Effects and Exerts Antitumor Activity".JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 350.1(2014):36-45.