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Degradador covalente del factor de transcripción oncogénico β-catenina
Flor A Gowans1,2, Nafsika Forte1,2, Justin Hatcher1,2
1Department of Chemistry, University of California, Berkeley, California 94720, United States.
Journal of the American Chemical Society
|June 7, 2024
Resumen
Los investigadores desarrollaron EN83, un nuevo compuesto que degrada el factor de transcripción oncogénico beta-catenina (CTNNB1) a través de una vía dependiente del proteasoma. Este enfoque de orientación covalente ofrece una nueva estrategia para la terapia del cáncer.
Área de la Ciencia:
- En el campo de la oncología
- Biología molecular
- Descubrimiento de drogas
Sus antecedentes:
- La beta-catenina (CTNNB1) es un factor de transcripción oncogénico clave implicado en la patogénesis del cáncer.
- La orientación farmacológica de CTNNB1 ha sido un desafío significativo en la investigación del cáncer.
Objetivo del estudio:
- Identificar nuevos compuestos capaces de degradar el CTNNB1.
- Explorar estrategias de orientación covalente para desafiar los factores de transcripción.
Principales métodos:
- Detección de ligandos covalentes reactivos a la cisteína.
- Identificación y caracterización del degradador monovalente EN83.
- Optimización estructural del compuesto de plomo.
Principales resultados:
- EN83 fue identificado como un compuesto que agota CTNNB1 a través de la degradación ubiquitina-proteasoma.
- EN83 se dirige covalentemente a CTNNB1 en las cisteínas C466, C520 y C619, causando desestabilización.
- Un degradador optimizado apunta selectivamente al C619, lo que demuestra una alta potencia.
Conclusiones:
- Los enfoques quimioproteómicos pueden apuntar y degradar con éxito factores de transcripción desafiantes como CTNNB1.
- La degradación mediada por la desestabilización es una estrategia viable para desarrollar nuevas terapias contra el cáncer.
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