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Modificación covalente quimioselectiva de K-Ras (G12R) con un electrófilo de molécula pequeña
Ziyang Zhang1,2, Johannes Morstein1, Andrew K Ecker1
1Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California 94158, United States.
Journal of the American Chemical Society
|August 24, 2022
Resumen
Los investigadores descubrieron nuevos ligandos covalentes dirigidos a la mutación K-Ras (G12R), un conductor común del cáncer. Este avance permite la inhibición selectiva de este mutante KRAS específico, allanando el camino para nuevas terapias contra el cáncer.
Área de la Ciencia:
- En el campo de la oncología
- Química medicinal
- Biología molecular
Sus antecedentes:
- Las mutaciones KRAS son conductores frecuentes de cánceres humanos.
- Dirigirse a las mutaciones KRAS con inhibidores de moléculas pequeñas es una estrategia terapéutica clave.
- El desarrollo de inhibidores específicos del alelo para los mutantes KRAS más allá de G12C sigue siendo un desafío significativo.
Objetivo del estudio:
- Para descubrir ligandos químicos covalentes dirigidos al mutante oncogénico K-Ras (G12R).
- Para explorar el mecanismo de unión covalente al residuo de arginina en K-Ras ((G12R).
- Establecer una base para el desarrollo de terapias específicas de mutantes para los cánceres impulsados por K-Ras (G12R).
Principales métodos:
- El descubrimiento de los ligandos químicos covalentes.
- Ensayos bioquímicos para evaluar la unión y la reactividad de los ligandos.
- Cristalografía de rayos X para determinar el modo de unión y el adducto químico.
Principales resultados:
- Identificación de los ligandos covalentes que se unen a la bolsa Switch II de K-Ras ((G12R).
- Demostración de una reacción irreversible con el residuo de arginina mutante (Arginina 12).
- La estructura cristalina de rayos X reveló un producto de condensación de imidazolio formado entre el ligando y la arginina.
Conclusiones:
- Los residuos de arginina pueden ser dirigidos selectivamente por electrófilos de moléculas pequeñas.
- Los ligandos descubiertos proporcionan una base para el desarrollo de terapias contra los cánceres K-Ras (G12R).
- Este trabajo expande la drogabilidad de los mutantes KRAS más allá de la variante G12C.
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