title: Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices.
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.
authors.affiliation: Department of Pediatric Oncology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215; and.
authors.forename: Elizaveta S
authors.initials: ES
authors.lastname: Leshchiner
authors.affiliation: Department of Genetics and.
authors.forename: Andrey
authors.initials: A
authors.lastname: Parkhitko
authors.affiliation: Department of Pediatric Oncology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215; and.
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Bird
authors.affiliation: Department of Pediatric Oncology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215; and.
authors.forename: James
authors.initials: J
authors.lastname: Luccarelli
authors.affiliation: Department of Pediatric Oncology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215; and.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Bellairs
authors.affiliation: Department of Pediatric Oncology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215; and.
authors.forename: Silvia
authors.initials: S
authors.lastname: Escudero
authors.affiliation: Department of Pediatric Oncology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215; and.
authors.forename: Kwadwo
authors.initials: K
authors.lastname: Opoku-Nsiah
authors.affiliation: Department of Pediatric Oncology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215; and.
authors.forename: Marina
authors.initials: M
authors.lastname: Godes
authors.affiliation: Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115.
authors.forename: Norbert
authors.initials: N
authors.lastname: Perrimon
authors.affiliation: Department of Pediatric Oncology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215; and loren_walensky@dfci.harvard.edu.
authors.forename: Loren D
authors.initials: LD
authors.lastname: Walensky
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002850:Chromatography, Gel; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster; D004926:Escherichia coli; D005453:Fluorescence; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology*; D009682:Magnetic Resonance Spectroscopy; D044085:Microfluidics; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D017433:Protein Structure, Secondary / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D020837:SOS1 Protein / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; C117307:KRAS protein, human; D010455:Peptides; D011518:Proto-Oncogene Proteins; D020837:SOS1 Protein; D016283:Proto-Oncogene Proteins p21(ras); C417283:Ras85D protein, Drosophila; D018631:ras Proteins
keywords: RAS; SOS1; cancer; inhibitor; stapled peptide