Abstract :
The characterization of oncogenic driver mutations has revolutionized cancer biology, but certain genetic alterations—such as KRAS, NRAS, and MYC—remained long considered “undruggable” due to structural and functional constraints. Recent advances in structural biology, covalent inhibitor design, and targeted protein degradation have transformed this paradigm, leading to the development of selective agents against previously elusive targets. KRAS mutations, particularly KRAS^G12C^, have emerged as prominent therapeutic candidates with the advent of covalent inhibitors such as Sotorasib and Adagrasib, which exploit unique allosteric pockets. Parallel innovations, including PROTAC technology, synthetic lethality strategies, and RNA-based therapeutics, further expand the therapeutic landscape. Despite encouraging clinical activity, resistance mechanisms—both adaptive and acquired—pose significant challenges, necessitating rational combination therapies and biomarker-driven patient selection. This review summarizes the evolution from “undruggable” to “drugged” targets, highlights the structural and biochemical breakthroughs enabling KRAS inhibition, and explores the future directions of integrating these agents into precision oncology frameworks.
Keyword :
KRAS inhibitors, Undruggable targets, Precision oncology, Sotorasib, Adagrasib, PROTACs, Synthetic lethality, Targeted protein degradation, Covalent inhibitors, Cancer therapeutics, Oncogenic driver mutations, Resistance mechanisms, RAS pathway.