Proceedings of the National Academy of Sciences | 2021
A Sos proteomimetic as a pan-Ras inhibitor
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. Aberrant Ras signaling is linked to a wide spectrum of hyperproliferative diseases, and components of the signaling pathway, including Ras, have been the subject of intense and ongoing drug discovery efforts. The cellular activity of Ras is modulated by its association with the guanine nucleotide exchange factor Son of sevenless (Sos), and the high-resolution crystal structure of the Ras–Sos complex provides a basis for the rational design of orthosteric Ras ligands. We constructed a synthetic Sos protein mimic that engages the wild-type and oncogenic forms of nucleotide-bound Ras and modulates downstream kinase signaling. The Sos mimic was designed to capture the conformation of the Sos helix–loop–helix motif that makes critical contacts with Ras in its switch region. Chemoproteomic studies illustrate that the proteomimetic engages Ras and other cellular GTPases. The synthetic proteomimetic resists proteolytic degradation and enters cells through macropinocytosis. As such, it is selectively toxic to cancer cells with up-regulated macropinocytosis, including those that feature oncogenic Ras mutations.