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La inhibición de la tanquirasas estabiliza la axina y antagoniza la señalización Wnt
Shih-Min A Huang1, Yuji M Mishina, Shanming Liu
1Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
Nature
|September 18, 2009
Resumen
Una nueva molécula, XAV939, se dirige al cáncer mediante la estabilización de la axina, una proteína clave en la vía Wnt. Esto promueve la degradación de la beta-catenina, inhibiendo el crecimiento del cáncer y ofreciendo nuevas estrategias terapéuticas.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Biología del cáncer Biología del cáncer.
- Descubrimiento de Drogas Descubrimiento de Drogas
Sus antecedentes:
- La vía Wnt es crucial para el desarrollo celular y con frecuencia está desregulada en los cánceres.
- La estabilidad de la beta-catenina está estrechamente controlada por el complejo de destrucción, por lo que es un objetivo de cáncer.
- Dirigirse a la vía Wnt es un desafío debido a los limitados componentes farmacológicos.
Objetivo del estudio:
- Para identificar pequeñas moléculas que inhiben la transcripción mediada por beta-catenina.
- Para aclarar el mecanismo de acción de los nuevos inhibidores de la vía Wnt.
Principales métodos:
- Pantalla genética química para identificar el XAV939.9.
- Proteómica química cuantitativa para identificar objetivos XAV939.
- Análisis de la homeostasis de la proteína axina y las vías de degradación.
Principales resultados:
- XAV939 inhibe selectivamente la transcripción de la beta-catenina mediante la estabilización de la axina.
- XAV939 inhibe la tanquerasa 1 y la tanquerasa 2, enzimas que promueven la degradación de la axina.
- La inhibición de la tanquirasas conduce a un aumento de los niveles de axina y la degradación de la beta-catenina a través de la vía ubiquitina-proteasoma.
Conclusiones:
- XAV939 proporciona una nueva estrategia terapéutica al dirigirse a la estabilidad de la axina.
- La inhibición de la tanquirasa ofrece un nuevo enfoque para la terapia del cáncer impulsada por la vía Wnt.
- Comprender la regulación de la axina abre nuevas vías para el tratamiento del cáncer.
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