KRas is the most frequently mutated oncogene in human cancer, and even 40 years after the initial discovery of Ras oncogenes in 1982, no approved drug directly targets Ras in Ras-driven cancer. New information and approaches for direct targeting of mutant Ras have fueled hope for the development of direct KRas inhibitors. In this review, we provide a comprehensive historical perspective of the development of promising KRasG12C inhibitors that covalently bind to the mutated cysteine residue in the switch-II pocket and trap the protein in the inactive GDP bound state. After decades of failure, three covalent G12C-specific inhibitors from three independent companies have recently entered clinical trials and therefore represent new hope for patients suffering from KRasG12C driven cancer.
This journal is © The Royal Society of Chemistry 2020.