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La proteína fosfatasa 5 recluta quimeras para acelerar la desfosforilación de la quinasa 1 regulada por la señal de

Qiuyue Zhang^1,2, Xuexuan Wu^1,2, Hengheng Zhang^1,2

¹State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.

Journal of the American Chemical Society

|December 22, 2022

Resumen

Los investigadores desarrollaron DDO3711, una nueva quimera que recluta PP5 para desfosforilar p-ASK1 ((T838), reduciendo efectivamente la progresión del cáncer gástrico. Este enfoque dirigido es prometedor para regular las oncoproteínas anormalmente fosforiladas.

Área de la Ciencia:

Biología molecular
En el campo de la oncología
La bioquímica

Sus antecedentes:

La fosforilación proteica aberrante, particularmente la hiperfosforilación de las oncoproteínas como ASK1, impulsa la progresión del cáncer.
PP5 normalmente desfosforila p-ASK1 ((T838), pero su actividad está inhibida en los tumores, lo que lleva a niveles elevados de p-ASK1 ((T838).
Dirigirse a la desfosforilación de proteínas ofrece una estrategia para el tratamiento del cáncer.

Objetivo del estudio:

Diseñar y validar las quimeras de reclutamiento de fosfatasa (PHORC) para la desfosforilación dirigida de p-ASK1 ((T838).
Desarrollar una nueva estrategia terapéutica para el cáncer gástrico mediante la restauración de la homeostasis por fosforilación de ASK1.

Principales métodos:

Diseño de DDO3711, un PHORC que incluye un inhibidor de ASK1 vinculado a un activador de PP5.
Experimentos in vitro e in vivo para evaluar la eficacia de DDO3711 en la reducción de los niveles de p-ASK1
Pruebas de actividad antiproliferativa con células de cáncer gástrico MKN45.

Principales resultados:

DDO3711 redujo efectivamente los niveles de p-ASK1 (T838) in vitro e in vivo.
DDO3711 demostró una actividad antiproliferativa significativa contra las células MKN45 (CI50 = 0,5 μM) a través de un mecanismo de unión directa y mediado por proximidad.
Ni el inhibidor ASK1 ni el activador PP5, solos o combinados, mostraron efectos sobre las células MKN45, lo que pone de relieve la necesidad de la estructura PHORC.

Conclusiones:

Los PHORC, ejemplificados por DDO3711, son herramientas efectivas para acelerar la desfosforilación de proteínas dirigidas.
Este enfoque proporciona una nueva estrategia para la regulación precisa de la fosforilación de las oncoproteínas.
Los hallazgos apoyan el potencial de los PHORC en el desarrollo de nuevas terapias para los cánceres impulsados por una fosforilación anormal.

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