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

•In this review, we mainly highlight the drug design, development process, and history of KRASG12C inhibitors.•Targeting KRAS mutant with covalent G12C specific inhibitors is an attractive strategy because of the high prevalence of KRASG12C mutations and their importance in initiating and sustaining tumor growth.•Recently, the FDA granted accelerated approval to Sotorasib and Adagrasib, both RAS GTPase family inhibitors, for adult patients with KRASG12C-mutated locally advanced or metastatic lung cancer. KRASG12C 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. KRASG12C 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 KRASG12C 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 KRASG12C. In this review, we focus on the design, development, and history of KRASG12C inhibitors.