Structural insights into small-molecule KRAS inhibitors for targeting KRAS mutant cancers

The Kirsten rat sarcoma viral (KRAS) oncogene is the most frequently mutated isoform of RAS, associated with 85 % of RAS-driven cancers. KRAS functions as a signaling hub, participating in various cellular signaling pathways and regulating a wide range of important activities, including cell proliferation, differentiation, growth, metabolism, and migration. Despite being the most frequently altered oncogenic protein in solid tumors, over the past four decades, KRAS has historically been considered "undruggable" owing to a lack of pharmacologically targetable pockets within the mutant isoforms. However, improvements in drug design and development have culminated in the development of selective inhibitors for KRAS mutants. Recent developments have led to the successful targeting of the KRAS