A Sos proteomimetic as a pan-Ras inhibitor

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 ex...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 118; no. 18; pp. 1 - 11
Main Authors Hong, Seong Ho, Yoo, Daniel Y., Conway, Louis, Richards-Corke, Khyle C., Parker, Christopher G., Arora, Paramjit S.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 04.05.2021
Subjects
Biological Sciences
Crystal structure
Guanine
Guanine nucleotide exchange factor
Kinases
Mutation
Nucleotides
Physical Sciences
Proteolysis
Ras protein
Signal transduction
Signaling
peptide
proteomimetic
Ras
Sos
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Summary: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.
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Edited by Daniel-Adriano Silva, Neoleukin Therapeutics, Seattle, WA, and accepted by Editorial Board Member Stephen J. Benkovic March 19, 2021 (received for review January 18, 2021)
1S.H.H. and D.Y.Y. contributed equally to this work.
Author contributions: S.H.H., D.Y.Y., and P.S.A. designed research; S.H.H., D.Y.Y., L.C., K.C.R.-C., and C.G.P. performed research; S.H.H., D.Y.Y., L.C., C.G.P., and P.S.A. analyzed data; and S.H.H., D.Y.Y., and P.S.A. wrote the paper.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.2101027118