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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