PNAS 2015-02-10

Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices.

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

Index: Proc. Natl. Acad. Sci. U. S. A. 112(6) , 1761-6, (2015)

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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.