A Sos proteomimetic as a pan-Ras inhibitor

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Abstract
Significance: Oncogenic Ras isoforms are the subject of intense study due to the difficulty in targeting these biomedically important yet “undruggable” proteins. Recent success in covalent targeting of a Ras mutant illustrates avenues for ligand design; however, many mutant Ras forms do not feature appropriately-placed nucleophiles, suggesting that strategies for noncovalent engagement of Ras are required. We report the design of a conformationally-defined proteomimetic that reproduces a key binding surface of Sos, a well-characterized effector of Ras. The proteomimetic binds wild-type and various mutant forms of Ras and modulates downstream signaling. Significantly, the compound shows enhanced internalization and selective toxicity toward cancer cells that up-regulate macropinocytosis. We anticipate these studies will foster new therapeutic modalities to engage mutant Ras.
Funding Information
  • HHS | NIH | National Institute of General Medical Sciences (R35GM130333)

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