Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices

Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1761-6. doi: 10.1073/pnas.1413185112. Epub 2015 Jan 26.

Abstract

Activating mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) underlie the pathogenesis and chemoresistance of ∼ 30% of all human tumors, yet the development of high-affinity inhibitors that target the broad range of KRAS mutants remains a formidable challenge. Here, we report the development and validation of stabilized alpha helices of son of sevenless 1 (SAH-SOS1) as prototype therapeutics that directly inhibit wild-type and mutant forms of KRAS. SAH-SOS1 peptides bound in a sequence-specific manner to KRAS and its mutants, and dose-responsively blocked nucleotide association. Importantly, this functional binding activity correlated with SAH-SOS1 cytotoxicity in cancer cells expressing wild-type or mutant forms of KRAS. The mechanism of action of SAH-SOS1 peptides was demonstrated by sequence-specific down-regulation of the ERK-MAP kinase phosphosignaling cascade in KRAS-driven cancer cells and in a Drosophila melanogaster model of Ras85D(V12) activation. These studies provide evidence for the potential utility of SAH-SOS1 peptides in neutralizing oncogenic KRAS in human cancer.

Keywords: RAS; SOS1; cancer; inhibitor; stapled peptide.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Line, Tumor
  • Chromatography, Gel
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster
  • Escherichia coli
  • Fluorescence
  • Gene Expression Regulation, Enzymologic / physiology*
  • Humans
  • MAP Kinase Signaling System / genetics
  • MAP Kinase Signaling System / physiology*
  • Magnetic Resonance Spectroscopy
  • Microfluidics
  • Mutation / genetics
  • Peptides / genetics
  • Peptides / metabolism
  • Peptides / pharmacology*
  • Protein Binding
  • Protein Structure, Secondary / genetics
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins p21(ras)
  • SOS1 Protein / genetics
  • SOS1 Protein / metabolism*
  • ras Proteins / antagonists & inhibitors*
  • ras Proteins / genetics
  • ras Proteins / metabolism*

Substances

  • Drosophila Proteins
  • KRAS protein, human
  • Peptides
  • Proto-Oncogene Proteins
  • SOS1 Protein
  • Proto-Oncogene Proteins p21(ras)
  • Ras85D protein, Drosophila
  • ras Proteins