Recent progress in targeting KRAS mutant cancers with covalent G12C-specific inhibitors

KRAS^G12C has been identified as a potential target in the treatment of solid tumors. One of the most often transformed proteins in human cancers is the small Kirsten rat sarcoma homolog (KRAS) subunit of GTPase, which is typically the oncogene driver. KRAS^G12C is altered to keep the protein in an active GTP-binding form. KRAS has long been considered an 'undrugable' target, but sustained research efforts focusing on the KRAS^G12C mutant cysteine have achieved promising results. For example, the US Food and Drug Administration (FDA) has passed emergency approval for sotorasib and adagrasib for the treatment of metastatic lung cancer. Such achievements have sparked several original approaches to KRAS^G12C. In this review, we focus on the design, development, and history of KRAS^G12C inhibitors.