期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：6
页码：1761-1766
DOI：10.1073/pnas.1413185112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceKRAS is one of the most prevalent and vicious oncogenic proteins, yet no drugs are available to inhibit its pathologic activity in patients. We report that KRAS-targeting stapled peptides, modeled after the native son of sevenless 1 (SOS1) helical domain, engage wild-type and clinically relevant KRAS mutant proteins with nanomolar affinity. To our knowledge, these compounds represent the highest affinity and broadest spectrum binders of KRAS mutants reported to date. The stapled peptides disrupt the SOS1/KRAS protein interaction and directly inhibit nucleotide association to wild-type and mutant KRAS proteins. We correlate functional binding activity with SAH-SOS1 cytotoxicity across a 13-member panel of KRAS-driven cancer cells and demonstrate sequence- and dose-dependent inhibition of the ERK-MAP kinase phosphosignaling cascade downstream of KRAS in vitro and in vivo. 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.
关键词：RAS ; inhibitor ; SOS1 ; stapled peptide ; cancer
