A Comprehensive Review of Marketed KRAS Inhibitors and Degraders: Challenges and Opportunities.

The rat sarcoma virus oncogene (RAS) is one of the most frequently mutated drivers in human cancers. Developing targeted therapies against RAS has been challenging due to its structure. The recent breakthroughs with covalent Kirsten RAS (KRAS) inhibitors represent a key milestone in targeting mutant KRAS proteins. However, drug resistance remains a significant obstacle. The proteolysis-targeting chimeras (PROTACs), which degrade mutant KRAS proteins, offer a promising strategy to overcome resistance and expand therapeutic options. This review covers the structural basis of KRAS and signaling networks, while discussing recent advancements in KRAS inhibitor research and PROTAC technology. It aims to provide a foundation and inspiration for future KRAS inhibitor and degrader development.