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Una interfaz de proteína neomorfa cataliza la inhibición covalente del ácido aspártico en los tumores

Caroline Weller¹, G Leslie Burnett¹, Lingyan Jiang¹

¹Revolution Medicines, Inc., Redwood City, CA, USA.

Science (New York, N.Y.)

|July 24, 2025

Resumen

Los investigadores desarrollaron nuevos inhibidores covalentes dirigidos al cáncer KRAS ^G12D mediante la creación de una interacción proteica única. Este enfoque permite la administración de fármacos potentes, lo que es prometedor en los modelos preclínicos de cáncer.

Área de la Ciencia:

En el campo de la oncología
Biología molecular
Descubrimiento de drogas

Sus antecedentes:

Las proteínas RAS mutantes, particularmente KRAS ^G12D, son factores clave en numerosos cánceres humanos.
Dirigirse a KRAS^G12D con inhibidores covalentes es un desafío debido a la baja reactividad y la alta abundancia de moléculas similares en el cuerpo.

Objetivo del estudio:

Para superar los desafíos en la orientación covalente KRAS^G12D.
Desarrollar nuevos inhibidores con mayor selectividad y eficacia contra los cánceres inducidos por KRAS^G12D.

Principales métodos:

Compuestos desarrollados que se unen a la ciclofilina A (CYPA).
Diseñado una nueva interfaz proteína-proteína entre CYPA y RAS activo.
Utilizó esta interfaz para mejorar la velocidad de reacción de inhibidores covalentes con baja reactividad intrínseca.

Principales resultados:

Se logró una mejora selectiva de la velocidad similar a la enzima para la modificación covalente de RAS^G12D.
Se han desarrollado compuestos biodisponibles por vía oral que muestran una actividad antitumoral significativa en modelos preclínicos.
Identificado el zoldonrasib (RMC-9805) como un agente investigativo prometedor actualmente en ensayos clínicos.

Conclusiones:

La estrategia vinculante de CYPA-RAS supera efectivamente las limitaciones al dirigirse a KRAS^G12D.
Este enfoque produce inhibidores covalentes potentes y selectivos para los cánceres impulsados por KRAS^G12D.
Los hallazgos apoyan el desarrollo clínico de nuevas terapias para desafiar las mutaciones del cáncer.

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