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La inhibición selectiva del CRAF provoca la transaccionalidad
Charles W Morgan1, Ian L Dale2, Andrew P Thomas3
1Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.
Journal of the American Chemical Society
|March 22, 2021
Resumen
Dirigirse selectivamente a CRAF (una quinasa RAF) puede activar paradójicamente la señalización RAF, contrariamente a las hipótesis. Este estudio utilizó el ligando bioortogonal (BOLT) para investigar la inhibición de CRAF, revelando implicaciones para el descubrimiento de fármacos contra el cáncer.
Área de la Ciencia:
- En el campo de la oncología
- Biología molecular
- Farmacología
Sus antecedentes:
- El descubrimiento de fármacos específicos de la isoforma es difícil, con consecuencias desconocidas de la regulación de la isoforma.
- Las quinasas RAF (BRAF, CRAF) son clave en la señalización de la quinasas MAP y a menudo mutan en el cáncer.
- Los inhibidores actuales de RAF pueden causar una activación paradójica a través de CRAF, lo que lleva a la resistencia.
Objetivo del estudio:
- Investigar los efectos de la inhibición selectiva del CRAF.
- Explorar si la inhibición selectiva del CRAF evita la activación paradójica.
- Demostrar la utilidad del enlace de ligando bioortogonal (BOLT) para la validación del objetivo.
Principales métodos:
- Se utilizó el enlace bioortogonal de ligandos (BOLT) para dirigir selectivamente los inhibidores al CRAF.
- Investigó las consecuencias de la señalización de la inhibición selectiva de CRAF.
Principales resultados:
- Se encontró que la inhibición selectiva de CRAF promueve la activación paradójica de la señalización RAF.
- Este hallazgo desafía la hipótesis de que la inhibición selectiva del CRAF evitaría la activación paradójica.
- BOLT demostrado como un método para la clasificación de objetivos en etapa temprana en el descubrimiento de fármacos.
Conclusiones:
- La inhibición selectiva de CRAF puede conducir a una activación paradójica, similar a la inhibición más amplia de RAF.
- BOLT es una herramienta valiosa para evaluar las consecuencias de apuntar a isoformas de proteínas específicas al principio del descubrimiento de fármacos.
- Comprender el papel de CRAF es crucial para desarrollar terapias efectivas contra el cáncer y superar la resistencia a los medicamentos.
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