Remodelación química de una chaperona celular para dirigirse al estado activo del KRAS mutante

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Christopher J Schulze¹, Kyle J Seamon¹, Yulei Zhao²

¹Department of Biology, Revolution Medicines, Inc., Redwood City, CA 94063, USA.

Science (New York, N.Y.)

|August 17, 2023

Resumen

Los investigadores desarrollaron una nueva molécula pequeña para atacar KRAS G12C, una mutación común que conduce al cáncer. Este medicamento crea un nuevo sitio de unión a la ciclofilina A, inhibiendo efectivamente el crecimiento del cáncer y conduciendo a la regresión tumoral en los modelos.

Área de la Ciencia:

En el campo de la oncología
Biología molecular
Descubrimiento de drogas

Sus antecedentes:

Muchas proteínas, incluido KRAS, carecen de bolsas de unión adecuadas para los inhibidores de moléculas pequeñas, clasificándolas como "indruggables".
El KRAS mutante es un factor clave en numerosos cánceres, pero su estado activo sigue siendo un objetivo terapéutico desafiante.
Se necesitan estrategias innovadoras para atacar proteínas con sitios de unión de difícil acceso.

Objetivo del estudio:

Diseñar una nueva molécula pequeña que pueda crear una interfaz farmacológica para apuntar al estado activo de KRAS G12C.
Evaluar la eficacia de esta nueva estrategia terapéutica en modelos preclínicos de cáncer.

Principales métodos:

Diseñó una pequeña molécula inspirada en productos naturales para remodelar la ciclofilina A (CYPA).
Creado un tricomplejo selectivo de alta afinidad de CYPA: droga: KRAS G12C.
Se evaluó la inhibición de la señalización oncogénica y la regresión tumoral en modelos de cáncer humano.

Principales resultados:

La pequeña molécula diseñada remodeló con éxito CYPA, formando una interfaz neomorfa para KRAS G12C.
El CYPA:drug:KRAS G12C tricomplex inactivó efectivamente las vías de señalización oncogénica.
Se observaron regresiones tumorales significativas en múltiples modelos de cáncer humano que albergaban mutaciones KRAS G12C.

Conclusiones:

Esta nueva estrategia inhibidora tricompleja proporciona un enfoque viable para dirigirse a los mutantes KRAS previamente no farmacológicos.
El enfoque tiene potencial para desarrollar terapias contra otros factores de cáncer no farmacológicos.
Los inhibidores mutantes KRAS G12C y multi-RAS basados en esta estrategia se encuentran actualmente en ensayos clínicos.

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