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A Sos proteomimetic as a pan-Ras inhibitor

Seong Ho Hong1, Daniel Y Yoo1, Louis Conway2

  • 1Department of Chemistry, New York University, New York, NY 10003.

Proceedings of the National Academy of Sciences of the United States of America
|April 30, 2021
PubMed

Insights

A synthetic mimic of the Son of sevenless (Sos) protein targets Ras signaling, offering a new therapeutic strategy for hyperproliferative diseases. This novel proteomimetic selectively kills cancer cells by disrupting Ras-Sos interactions and exploiting macropinocytosis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Drug Discovery

Background:

  • Aberrant Ras signaling drives hyperproliferative diseases, making Ras pathway components key targets for drug development.
  • The Son of sevenless (Sos) guanine nucleotide exchange factor modulates Ras cellular activity.
  • The Ras-Sos complex structure enables rational design of Ras-targeting ligands.

Purpose of the Study:

  • To design and construct a synthetic protein mimic of Sos.
  • To investigate the mimic's ability to engage Ras and modulate downstream signaling.
  • To evaluate the proteomimetic's cellular uptake, stability, and selective toxicity.

Main Methods:

  • Construction of a synthetic Sos protein mimic based on the Ras-Sos crystal structure.
  • Engagement studies using chemoproteomics to identify targeted GTPases.
  • Assessment of proteolytic stability and cellular entry via macropinocytosis.
  • Evaluation of selective toxicity in cancer cells with varying macropinocytosis levels.

Main Results:

  • The synthetic Sos mimic effectively engages wild-type and oncogenic Ras.
  • The proteomimetic modulates downstream kinase signaling pathways.
  • The mimic demonstrates resistance to degradation and cellular entry via macropinocytosis.
  • Selective toxicity was observed in cancer cells exhibiting upregulated macropinocytosis, including those with Ras mutations.

Conclusions:

  • A synthetic Sos mimic represents a promising therapeutic agent for Ras-driven cancers.
  • The proteomimetic's mechanism involves disrupting Ras-Sos interactions and leveraging macropinocytosis for targeted delivery.
  • This approach offers a novel strategy for treating hyperproliferative diseases linked to aberrant Ras signaling.
Keywords:
RasSospeptideproteomimetic

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