Evolution of direct RAS inhibitors: from undruggable target to clinical breakthroughs

The RAS signaling pathway, particularly through mutations in KRAS, NRAS, and HRAS, plays a pivotal role in driving oncogenesis in a wide range of cancers. For years, RAS proteins were deemed "undruggable" due to their smooth surface and lack of deep binding pockets. However, recent breakthroughs in targeting specific RAS mutations, particularly KRAS^G12C, have revolutionized the field. The discovery of covalent inhibitors that bind to an allosteric pocket near the cysteine residue of KRAS^G12C has led to the development of FDA-approved drugs, marking a significant milestone in RAS-targeted therapy. This review provides a comprehensive overview of the evolution of direct RAS inhibitors, focusing on the chemical development of small molecule inhibitors, molecular glues, protein degraders, and other emerging strategies. We highlight the structural evolution of KRAS inhibitors, from covalent fragment-based approaches to non-covalent inhibitors and pan-RAS targeting strategies. Additionally, we discuss the clinical progress of key inhibitors, including their efficacy, resistance mechanisms, and combination treatment options. Finally, this review explores other innovative approaches such as cyclopeptide inhibitors and outlines future directions of RAS-targeting strategies. The success of RAS-targeted therapies underscores the transformative potential of overcoming the "undruggable" nature of RAS, offering new hope for patients with RAS-driven cancers.