A Sos proteomimetic as a pan-Ras inhibitor

• Published in: Proceedings of the National Academy of Sciences - PNAS 2021-05, Vol.118 (18), p.1-11
• Main Authors: Hong, Seong Ho, Yoo, Daniel Y., Conway, Louis, Richards-Corke, Khyle C., Parker, Christopher G., Arora, Paramjit S.
• Format: Article
• Language: English
• Subjects: Biological Sciences; Crystal structure; Guanine; Guanine nucleotide exchange factor; Kinases; Mutation; Nucleotides; Physical Sciences; Proteolysis; Ras protein; Signal transduction; Signaling
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2101027118

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 upregulated macropinocytosis, including those that feature oncogenic Ras mutations.