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Los inhibidores de K-Ras (G12C) controlan alostéricamente la afinidad GTP y las interacciones efectoras
Jonathan M Ostrem1, Ulf Peters, Martin L Sos
11] Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, California 94158, USA [2].
Nature
|November 22, 2013
Resumen
Los investigadores desarrollaron nuevas moléculas pequeñas dirigidas a la mutación del cáncer K-Ras (G12C). Estos inhibidores se unen de manera irreversible, creando un nuevo sitio objetivo y ofreciendo una estrategia terapéutica específica para los mutantes.
Área de la Ciencia:
- Oncología Oncología.
- Biología Molecular Biología Molecular
- Descubrimiento de Drogas Descubrimiento de Drogas
Sus antecedentes:
- Las mutaciones somáticas en K-Ras son comunes en el cáncer, vinculadas a los malos resultados del tratamiento.
- Dirigirse directamente a K-Ras es un desafío debido a su alta afinidad por GTP / GDP y la falta de sitios alostéricos conocidos.
- Las mutaciones oncogénicas de K-Ras perjudican la hidrólisis de GTP, aumentando la proporción de Ras. activo ligado al GTP.
Objetivo del estudio:
- Desarrollar pequeñas moléculas que se dirijan selectivamente al mutante oncogénico K-Ras (G12C).
- Identificar y validar un nuevo sitio de unión alostérico en K-Ras (G12C).
Principales métodos:
- Desarrollo de inhibidores irreversibles de moléculas pequeñas específicos para K-Ras (G12C).
- Estudios cristalográficos para dilucidar el mecanismo de unión e identificar nuevas bolsas.
- Análisis bioquímicos para evaluar las interacciones de unión de nucleótidos y efectores.
Principales resultados:
- Se desarrollaron inhibidores irreversibles que se unen específicamente a K-Ras (G12C) a través de la cisteína mutante.
- La cristalografía reveló un nuevo bolsillo de unión debajo de la región switch-II.
- La unión del inhibidor interrumpe el switch-I y el switch-II, cambiando la preferencia de nucleótidos de GTP a GDP y perjudicando la unión de Raf.
Conclusiones:
- Se ha identificado y validado un nuevo sitio alostérico específico de mutantes en K-Ras (G12C).
- Estos hallazgos proporcionan una estrategia basada en la estructura para desarrollar terapias dirigidas contra los cánceres mutantes K-Ras (G12C).
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