Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices.
Proc Natl Acad Sci U S A
; 112(6): 1761-6, 2015 Feb 10.
Article
en En
| MEDLINE
| ID: mdl-25624485
ABSTRACT
Activating mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) underlie the pathogenesis and chemoresistance of â¼ 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.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Péptidos
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Regulación Enzimológica de la Expresión Génica
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Proteínas Proto-Oncogénicas
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Proteínas ras
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Sistema de Señalización de MAP Quinasas
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Proteína SOS1
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Proteínas de Drosophila
Límite:
Animals
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Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2015
Tipo del documento:
Article