An engineered chimeric toxin that cleaves activated mutant and wild-type RAS inhibits tumor growth.
Proc Natl Acad Sci U S A
; 117(29): 16938-16948, 2020 07 21.
Article
en En
| MEDLINE
| ID: mdl-32616570
ABSTRACT
Despite nearly four decades of effort, broad inhibition of oncogenic RAS using small-molecule approaches has proven to be a major challenge. Here we describe the development of a pan-RAS biologic inhibitor composed of the RAS-RAP1-specific endopeptidase fused to the protein delivery machinery of diphtheria toxin. We show that this engineered chimeric toxin irreversibly cleaves and inactivates intracellular RAS at low picomolar concentrations terminating downstream signaling in receptor-bearing cells. Furthermore, we demonstrate in vivo target engagement and reduction of tumor burden in three mouse xenograft models driven by either wild-type or mutant RAS Intracellular delivery of a potent anti-RAS biologic through a receptor-mediated mechanism represents a promising approach to developing RAS therapeutics against a broad array of cancers.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Endopeptidasas
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Proteínas ras
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Proteínas de Unión al GTP rap1
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Toxina Diftérica
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Proteolisis
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Neoplasias Experimentales
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Año:
2020
Tipo del documento:
Article