Preclinical Evaluation of SCC244 (Glumetinib), a Novel, Potent, and Highly Selective Inhibitor of c-Met in MET-dependent Cancer Models

doi:10.1158/1535-7163.MCT-17-0368

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	Preclinical Evaluation of SCC244 (Glumetinib), a Novel, Potent, and Highly Selective Inhibitor of c-Met in MET-dependent Cancer Models
	Ai, Jing1 ; Chen, Yi1 ; Peng, Xia 1; Ji, Yinchun 1; Xi, Yong 1; Shen, Yanyan 1; Yang, Xinying 1; Su, Yi 1; Sun, Yiming 1; Gao, Yinglei 1
刊名	MOLECULAR CANCER THERAPEUTICS
	2018-04
卷号	17 期号:4 页码:751-762
ISSN号	1535-7163
DOI	10.1158/1535-7163.MCT-17-0368
文献子类	Review
英文摘要	. Because the receptor tyrosine kinase c-Met plays a critical role in tumor growth, metastasis, tumor angiogenesis, and drug resistance, the c-Met axis represents an attractive therapeutic target. Herein, we report the first preclinical characterization of SCC244, a novel, potent, and highly selective inhibitor of c-Met kinase. SCC244 showed subnanomolar potency against c-Met kinase activity and high selectivity versus 312 other tested protein kinases, making it one of the most selective c-Met inhibitors described to date. Moreover, this inhibitor profoundly and specifically inhibits c-Met signal transduction and thereby suppresses the c-Met-dependent neoplastic phenotype of tumor and endothelial cells. In xenografts of human tumor cell lines or non-small cell lung cancer and hepatocellular carcinoma patient-derived tumor tissue driven by MET aberration, SCC244 administration exhibits robust antitumor activity at the well-tolerated doses. In addition, the in vivo antitumor activity of SCC244 involves the inhibition of c-Met downstream signaling via a mechanism of combined antiproliferation and antiangiogenic effects. The results of the current study provide a strong foundation for the clinical investigation of SCC244 in patients with tumors harboring c-Met pathway alterations. (C) 2017 AACR.
资助项目	"Personalized Medicines Molecular Signature-based Drug Discovery and Development," Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020000] ; "Personalized Medicines Molecular Signature-based Drug Discovery and Development," Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020103] ; Natural Science Foundation of China[81473243] ; Natural Science Foundation of China[81773762]
WOS关键词	HEPATOCYTE GROWTH-FACTOR ; RECEPTOR TYROSINE KINASE ; CELL LUNG-CANCER ; GASTRIC-CANCER ; HEPATOCELLULAR-CARCINOMA ; COLORECTAL-CANCER ; INVASIVE GROWTH ; SCATTER-FACTOR ; ACQUIRED-RESISTANCE ; SOLID TUMORS
WOS研究方向	Oncology
语种	英语
出版者	AMER ASSOC CANCER RESEARCH
WOS记录号	WOS:000429111900005
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279830]
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	Ai, Jing; Ding, Jian; Geng, Meiyu
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Dept Med Chem, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Ai, Jing,Chen, Yi,Peng, Xia,et al. Preclinical Evaluation of SCC244 (Glumetinib), a Novel, Potent, and Highly Selective Inhibitor of c-Met in MET-dependent Cancer Models[J]. MOLECULAR CANCER THERAPEUTICS,2018,17(4):751-762.
APA	Ai, Jing.,Chen, Yi.,Peng, Xia.,Ji, Yinchun.,Xi, Yong.,...&Geng, Meiyu.(2018).Preclinical Evaluation of SCC244 (Glumetinib), a Novel, Potent, and Highly Selective Inhibitor of c-Met in MET-dependent Cancer Models.MOLECULAR CANCER THERAPEUTICS,17(4),751-762.
MLA	Ai, Jing,et al."Preclinical Evaluation of SCC244 (Glumetinib), a Novel, Potent, and Highly Selective Inhibitor of c-Met in MET-dependent Cancer Models".MOLECULAR CANCER THERAPEUTICS 17.4(2018):751-762.