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G3BP1/2-Objetivo PROTAC interrumpe los gránulos de estrés La migracitosis dependiente de ATF4 como terapia contra el
Ting Dong1,2, Fabao Zhao3, Mengmeng Wang2
1State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 2A Nanwei Road, Xicheng District, Beijing 100050, China.
Journal of the American Chemical Society
|December 23, 2024
Resumen
Los nuevos compuestos dirigidos a los gránulos de estrés (SGs) inhiben el crecimiento del cáncer al bloquear la transferencia del factor de supervivencia ATF4 de los fibroblastos a las células tumorales. Este descubrimiento ofrece nuevas estrategias terapéuticas para el tratamiento del cáncer.
Área de la Ciencia:
- Biología celular
- Oncología molecular
- La bioquímica
Sus antecedentes:
- Los gránulos de estrés (SG) son estructuras citoplasmáticas dinámicas formadas bajo estrés celular.
- El factor de transcripción activador 4 (ATF4) se traduce preferentemente dentro de los SG para promover la supervivencia celular.
- El papel de los SG y ATF4 en la progresión del cáncer dentro del microambiente tumoral no se comprende completamente.
Objetivo del estudio:
- Investigar el papel de los gránulos de estrés en la proliferación de las células cancerosas.
- Para desarrollar pequeñas moléculas dirigidas a la dinámica SG para la terapia del cáncer.
- Para aclarar el mecanismo de la entrega de ATF4 a través de SG en el crecimiento del tumor mediado por fibroblastos.
Principales métodos:
- Diseño y síntesis de moléculas pequeñas (# 129 y PT-129) dirigidas a G3BP1/2.
- Inhibición de la formación de gránulos de tensión y desmontaje de SG preexistentes.
- Ensayos in vitro e in vivo para evaluar el efecto de PT-129 en el crecimiento de las células cancerosas y la progresión tumoral.
- Investigación de los mecanismos de entrega de ATF4 a través de la migracitosis.
Principales resultados:
- Los compuestos # 129 y PT-129 inhiben efectivamente la formación de SG y desmontan los SG existentes.
- La inhibición farmacológica de los SG por PT-129 suprimió el crecimiento de células cancerosas mediadas por fibroblastos in vitro.
- El tratamiento con PT-129 redujo el crecimiento tumoral in vivo.
- Los gránulos de estrés facilitan la entrega de ATF4 de los fibroblastos a las células tumorales a través de la migracitosis, que es interrumpida por PT-129.
Conclusiones:
- Los gránulos de estrés juegan un papel crítico en la promoción de la proliferación de células cancerosas mediante la mediación de la administración de ATF4.
- Dirigirse a G3BP1 / 2 y modular la dinámica de SG con compuestos como PT-129 presenta una estrategia terapéutica prometedora para el cáncer.
- Estos hallazgos proporcionan nuevos conocimientos moleculares sobre la función de la SG y su potencial terapéutico en oncología.
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