Small molecule MET kinase inhibitors: Evolution, rational design, and early clinical knowledge

The c-MET receptor tyrosine kinase is a key oncogenic driver in many types of cancer and thus a prime target for small-molecule inhibitor therapy. The story of the development of these inhibitors is traced here from initial, non-selective lead molecules such as K252a to the clinically approved drugs like Capmatinib and Tepotinib. We discuss the historical evolution, rational design principles, and clinical observations that have influenced the discipline, with a focus on the critical transition from broad-spectrum multi-kinase inhibitors to precisely targeted therapies. The article highlights how a refined understanding of structure-activity relationships, kinase conformations, and ADME properties has driven the optimization of inhibitors. A critical analysis of the failures of previous clinical trials underscores the crucial role of robust, biomarker-driven patient selection and the use of physiologically relevant preclinical models. Finally, the successful development of contemporary MET inhibitors for cancers with specific alterations, such as MET exon 14 skipping, serves as a paradigm of iterative oncology learning, wherein early failures have given rise to precision medicine and enhanced therapeutic outcomes.