Structural insights, regulation, and recent advances of RAS inhibitors in the MAPK signaling cascade: a medicinal chemistry perspective

The MAPK pathway has four main components: RAS, RAF, MEK, and ERK. Among these, RAS is the most frequently mutated protein and the leading cause of cancer. The three isoforms of the RAS gene are HRAS, NRAS, and KRAS. The KRAS gene is characterized by two splice variants, K-Ras4A and K-Ras4B. The occurrence of cancer often involves a mutation in both KRAS4A and KRAS4B. In this study, we have elucidated the mechanism of the RAS protein complex and the movement of switches I and II. Only two RAS inhibitors, sotorasib and adagrasib, have been approved by the FDA, and several are in clinical trials. This review comprises recent developments in synthetic RAS inhibitors, their unique properties, their importance in inhibiting RAS mutations, and the current challenges in developing new RAS inhibitors. This review will undoubtedly help researchers design novel RAS inhibitors.