Direct Inhibition of Oncogenic KRAS by Hydrocarbon-Stapled SOS1 Helices

Leshchiner, Elizaveta S.; Parkhitko, Andrey; Bird, Gregory; Luccarelli, James; Bellairs, Joseph A.; Escudero, Silvia; Opoku-Nsiah, Kwadwo; Godes, Marina; Perrimon, Norbert; Walensky, Loren

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Author

Leshchiner, Elizaveta S.

Parkhitko, Andrey

Bird, Gregory HARVARD

Luccarelli, James HARVARD

Bellairs, Joseph A.

Escudero, Silvia

Opoku-Nsiah, Kwadwo

Godes, Marina HARVARD

Perrimon, Norbert HARVARD

Walensky, Loren HARVARD

Published Version

https://doi.org/10.1073/pnas.1413185112

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Citation

Leshchiner, Elizaveta S., Andrey Parkhitko, Gregory Bird, James Luccarelli, Joseph A. Bellairs, Silvia Escudero, Kwadwo Opoku-Nsiah et al. "Direct Inhibition of Oncogenic KRAS by Hydrocarbon-Stapled SOS1 Helices." Proceedings of the National Academy of Sciences 112, no. 6 (2015): 1761-1766. DOI: 10.1073/pnas.1413185112

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 Ras85DV12 activation. These studies provide evidence for the potential utility of SAH-SOS1 peptides in neutralizing oncogenic KRAS in human cancer.