Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices
| Autor: | Silvia Escudero, Andrey A. Parkhitko, Norbert Perrimon, Loren D. Walensky, Marina Godes, James Luccarelli, Elizaveta S. Leshchiner, Gregory H. Bird, Kwadwo Opoku-Nsiah, Joseph A. Bellairs |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Magnetic Resonance Spectroscopy
endocrine system diseases MAP Kinase Signaling System Mutant Blotting Western Microfluidics Son of Sevenless medicine.disease_cause Fluorescence Gene Expression Regulation Enzymologic Protein Structure Secondary Proto-Oncogene Proteins p21(ras) Cell Line Tumor Proto-Oncogene Proteins medicine Escherichia coli Animals Drosophila Proteins Humans neoplasms Mutation Multidisciplinary biology Cancer Biological Sciences medicine.disease digestive system diseases 3. Good health respiratory tract diseases Drosophila melanogaster Cancer cell SOS1 biology.protein Cancer research Chromatography Gel ras Proteins KRAS Peptides SOS1 Protein Protein Binding |
| Zdroj: | OpenAIRE Europe PubMed Central |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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