%0 Journal Article %J Proc Natl Acad Sci U S A %D 2015 %T Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices. %A Leshchiner, Elizaveta S %A Parkhitko, Andrey %A Bird, Gregory H %A Luccarelli, James %A Bellairs, Joseph A %A Escudero, Silvia %A Opoku-Nsiah, Kwadwo %A Godes, Marina %A Perrimon, Norbert %A Walensky, Loren D %K Animals %K Blotting, Western %K Cell Line, Tumor %K Chromatography, Gel %K Drosophila melanogaster %K Drosophila Proteins %K Escherichia coli %K Fluorescence %K Gene Expression Regulation, Enzymologic %K Humans %K Magnetic Resonance Spectroscopy %K MAP Kinase Signaling System %K Microfluidics %K Mutation %K Peptides %K Protein Binding %K Protein Structure, Secondary %K Proto-Oncogene Proteins %K ras Proteins %K SOS1 Protein %X

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.

%B Proc Natl Acad Sci U S A %V 112 %P 1761-6 %8 2015 Feb 10 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/25624485?dopt=Abstract %R 10.1073/pnas.1413185112