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Supplementary Materials and Methods; Tables S1-S4; Figures S1-S2 from Preclinical Evaluation of SCC244 (Glumetinib), a Novel, Potent, and Highly Selective Inhibitor of c-Met in MET-dependent Cancer Models

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posted on 2023-04-03, 15:08 authored by Jing Ai, Yi Chen, Xia Peng, Yinchun Ji, Yong Xi, Yanyan Shen, Xinying Yang, Yi Su, Yiming Sun, Yinglei Gao, Yuchi Ma, Bing Xiong, Jingkang Shen, Jian Ding, Meiyu Geng

Table S1. Enzymatic activities of Compounds against human c-Met; Table S2. Profiling of SCC244 against 313 kinases in Eurofins; Table S3. Anti-proliferative activity of SCC244 on c-Met-addicted cell lines; Table S4. High efficiency of SCC244 in c-Met-dependent cancer cell line derived xenograft models; Figure S1. (A-D) SCC244 was well- tolerated in MKN-45(A&D), SNU-5(B), and EBC-1(C) xenograft models; Figure S2. Intratumoral c-Met expression in 4 NSCLC PDX model with MET aberration detected by immunoblotting prior to the treatment.

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Chinese Academy of Sciences

Natural Science Foundation of China

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ARTICLE ABSTRACT

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. Mol Cancer Ther; 17(4); 751–62. ©2017 AACR.

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    Molecular Cancer Therapeutics

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    Drug TargetsProtein kinase & phosphatase drug targetsSmall Molecule Agents

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