Elizaveta S Leshchiner, Andrey Parkhitko, Gregory H Bird, James Luccarelli, Joseph A Bellairs, Silvia Escudero, Kwadwo Opoku-Nsiah, Marina Godes, Norbert Perrimon, Loren D Walensky
Proceedings of the National Academy of Sciences of the United States of America 2015 Feb 10Activating 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.
Elizaveta S Leshchiner, Andrey Parkhitko, Gregory H Bird, James Luccarelli, Joseph A Bellairs, Silvia Escudero, Kwadwo Opoku-Nsiah, Marina Godes, Norbert Perrimon, Loren D Walensky. Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices. Proceedings of the National Academy of Sciences of the United States of America. 2015 Feb 10;112(6):1761-6
PMID: 25624485
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