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Aprovechando la ligasa E3 KEAP1 para la degradación de proteínas dirigida

Jieli Wei¹, Fanye Meng¹, Kwang-Su Park¹

¹Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.

Journal of the American Chemical Society

|September 14, 2021

Resumen

Este estudio introduce una nueva quimera dirigida a la proteólisis (PROTAC) que utiliza la ligasa KEAP1 E3 para la degradación dirigida de proteínas. El nuevo PROTAC, MS83, degrada efectivamente las proteínas BRD4 y BRD3 con mayor durabilidad y actividad antiproliferativa.

Área de la Ciencia:

La bioquímica
Biología molecular
Descubrimiento de drogas

Sus antecedentes:

Las quimeras dirigidas a la proteólisis (PROTAC) son una estrategia terapéutica emergente.
Los PROTAC utilizan el sistema ubiquitina-proteasoma (UPS) para la degradación dirigida de las proteínas.
Las ligasas E3 limitadas se utilizan actualmente en el desarrollo de PROTAC.

Objetivo del estudio:

Investigar el potencial de la ligasa KEAP1 E3 en la degradación de las proteínas mediada por PROTAC.
Desarrollar y caracterizar un nuevo PROTAC (MS83) dirigido a BRD4/3/2 utilizando KEAP1.
Evaluar la eficacia, la durabilidad y la actividad antiproliferativa de MS83 en comparación con los PROTAC existentes.

Principales métodos:

Diseño y síntesis de un PROTAC (MS83) mediante la vinculación de un ligando KEAP1 a un aglutinante BRD4/3/2.
Ensayos basados en células para evaluar la degradación de proteínas, incluida la concentración, el tiempo, el KEAP1 y la dependencia de UPS.
Comparación de MS83 con un PROTAC de reclutamiento de CRBN (dBET1) con respecto a la cinética de degradación y los efectos antiproliferativos.
Análisis de la degradación específica de la isoforma de BRD4.

Principales resultados:

MS83 redujo efectivamente los niveles de proteínas BRD4 y BRD3 de una manera dependiente de KEAP1 y UPS.
MS83 demostró una degradación más duradera de BRD4/3 en comparación con dBET1 en las células MDA-MB-468.
Se observó una degradación selectiva de la isoforma corta de BRD4 sobre la isoforma larga en las células MDA-MB-231.
MS83 exhibió una actividad antiproliferativa superior en comparación con dBET1.

Conclusiones:

La ligasa KEAP1 E3 puede ser aprovechada con éxito para la degradación proteica dirigida.
MS83 representa un PROTAC potente y selectivo con propiedades mejoradas con respecto a los agentes existentes.
Este trabajo amplía el repertorio de ligasa E3 para el desarrollo de PROTAC, ofreciendo nuevas posibilidades terapéuticas.

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