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

by Selleckchem | Aug 20 2023

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.

Comments:

The passage describes a preclinical study on a novel inhibitor called SCC244, which specifically targets the receptor tyrosine kinase c-Met. The c-Met axis is known to play a critical role in tumor growth, metastasis, angiogenesis, and drug resistance, making it an attractive therapeutic target for cancer treatment.

SCC244 demonstrated potent inhibitory activity against c-Met kinase, with subnanomolar potency. It also exhibited high selectivity for c-Met, showing minimal activity against 312 other tested protein kinases. This high selectivity makes SCC244 one of the most specific c-Met inhibitors known to date.

Furthermore, SCC244 effectively suppressed c-Met signal transduction, leading to the inhibition of c-Met-dependent neoplastic phenotypes in tumor and endothelial cells. In xenograft models using human tumor cell lines or patient-derived tumor tissue with MET aberrations, administration of SCC244 resulted in robust antitumor activity at well-tolerated doses.

The in vivo antitumor effects of SCC244 were attributed to the inhibition of c-Met downstream signaling pathways. This mechanism involved a combined impact of suppressing tumor cell proliferation and angiogenesis. Overall, the findings from this study provide a solid basis for further clinical investigation of SCC244 in patients with tumors harboring alterations in the c-Met pathway.

It's important to note that the information provided is based on a fictional study and should not be considered as real scientific findings. If you have any specific questions about c-Met or related topics, feel free to ask.