LAUSR

Significance RAS is mutated in nearly 20% of human cancers and has few direct, efficacious inhibitors. Here, we developed a synthetic protein, JAM20, to discover potential regions on RAS that may be used for inhibition. JAM20 robustly inhibited signaling mediated by multiple oncogenic KRAS, HRAS, and NRAS mutants. It bound to an epitope in the Switch I/II pocket that overlaps with previously developed small-molecule inhibitors whose efficacy in a mouse model has not been established. These findings validate targeting the Switch I/II region as an approach to inhibiting tumors driven by diverse oncogenic RAS mutants and demonstrate the utility of synthetic binding proteins as tools for drug discovery against difficult targets.