The Ras proteins are aberrantly activated in a wide range of human cancers, often endowing tumors with aggressive properties and resistance to therapy. Decades of effort to develop direct Ras inhibitors for clinical use have thus far failed, largely because of a lack of adequate small-molecule binding pockets on the Ras surface. Here, we report the discovery of Ras-binding miniproteins from a naive library, and their evolution to afford versions with mid-picomolar affinity to Ras.
