A Sos proteomimetic as a pan-Ras inhibitor

Seong Ho Hong, Daniel Y. Yoo, Louis Conway, Khyle C. Richards-Corke, Christopher G. Parker, Paramjit S. Arora

Research output: Contribution to journalArticlepeer-review

Abstract

Aberrant Ras signaling is linked to a wide spectrum of hyper-proliferative 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.

Original languageEnglish (US)
Article number2101027118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number18
DOIs
StatePublished - May 4 2021

Keywords

  • Peptide
  • Proteomimetic
  • Ras
  • Sos

ASJC Scopus subject areas

  • General

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