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La alquilación desnitrogenativa de K-Ras ((G12D) inhibe la señalización oncogénica en las células cancerosas
Qinheng Zheng1, Kevan M Shokat1,2
1Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, California 94158, United States.
Journal of the American Chemical Society
|June 30, 2025
Resumen
Los investigadores desarrollaron nuevos compuestos dirigidos a las mutaciones K-Ras (G12D), una causa común de cáncer de páncreas. Estos fármacos inhiben selectivamente el crecimiento de las células cancerosas sin afectar a las células sanas u otras mutaciones de K-Ras.
Área de la Ciencia:
- En el campo de la oncología
- Química medicinal
- Biología molecular
Sus antecedentes:
- El adenocarcinoma ductal pancreático (PDAC) es un cáncer altamente letal, impulsado predominantemente por mutaciones KRAS.
- K-Ras ((G12D) es el factor oncogénico más frecuente en PDAC, sin embargo, carece de terapias dirigidas.
- Los esfuerzos actuales de descubrimiento de fármacos no han producido tratamientos aprobados que se dirijan directamente a K-Ras (G12D) de manera selectiva.
Objetivo del estudio:
- Desarrollar nuevos inhibidores selectivos de los mutantes para K-Ras (G12D).
- Explorar una nueva estrategia de orientación covalente para las proteínas oncogénicas.
- Para identificar compuestos que inhiben la proliferación de células cancerosas impulsadas por KRAS ((G12D).
Principales métodos:
- Síntesis y cribado de compuestos de α-diazoacetamida para la inhibición covalente.
- Mecanismo de alquilación desnitrogenativa dirigido al ácido aspártico en el sitio de la mutación.
- Evaluación de la eficacia del compuesto en KRAS ((G12D) mutante frente al tipo salvaje y otras líneas celulares de cáncer mutante.
Principales resultados:
- Una serie de compuestos de α-diazoacetamida demostró la inhibición selectiva de K-Ras ((G12D).
- El compuesto de plomo inhibe alostéricamente la vía MAPK aguas abajo de K-Ras.
- El mecanismo de ligadura covalente muestra selectividad para el ácido aspártico sobre otros nucleófilos como la cisteína.
- El enfoque evita las mutaciones K-Ras y K-Ras ((G12C) de tipo salvaje.
Conclusiones:
- Los nuevos compuestos de α-diazoacetamida ofrecen una estrategia prometedora para dirigirse a K-Ras ((G12D).
- El mecanismo covalente desarrollado amplía el alcance de los aminoácidos objetivo, incluidos los ácidos aspartico y glutámico.
- Esta investigación abre nuevas vías para el desarrollo de terapias contra los cánceres mutantes KRAS.
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