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El descubrimiento de bolsas de enlace inexploradas en ligases E3 conduce a la identificación de moduladores

Míriam Martínez-Cartró^1,2, Álvaro Serrano-Morrás^1,2, Andrea Bertran-Mostazo^1,2

¹Departament de Farmàcia i Tecnologia Farmacéutica, i Fisicoquímica. Facultat de Farmàcia i Ciències de l'Alimentació Universitat de Barcelona, Barcelona, 08028, Spain.

Advanced science (Weinheim, Baden-Wurttemberg, Germany)

|August 20, 2025

Resumen

Los investigadores identificaron bolsas alostéricas en las ligasas E3, cruciales para la degradación dirigida de las proteínas. Descubrieron nuevas moléculas pequeñas dirigidas a FBW7, que mejoran la degradación de las proteínas c-MYC y c-JUN.

Área de la Ciencia:

Bioquímica y Biología Molecular
Descubrimiento y desarrollo de fármacos
Biología Química

Sus antecedentes:

Las ligasas E3 son reguladores centrales del sistema ubiquitina-proteasoma (UPS), lo que las convierte en objetivos clave para las estrategias terapéuticas.
La degradación proteica dirigida (TPD) utiliza ligandos para las ligasas E3, pero solo unas pocas ligasas E3 tienen moduladores de moléculas pequeñas conocidos.
La identificación de nuevos sitios ligantables en las ligasas E3 es fundamental para la expansión de las aplicaciones de TPD.

Objetivo del estudio:

Desarrollar un método eficiente para la identificación de las superficies ligantables en diversas ligasas E3.
Descubrir nuevas moléculas pequeñas que se unen y modulan la actividad de la ligasa E3, específicamente dirigidas a los bolsillos alostéricos.
Demostrar el potencial terapéutico de los moduladores alostéricos de la ligasa E3 en el TPD.

Principales métodos:

Cribado computacional de 22 ligasas E3 estructuralmente distintas para identificar posibles bolsas de unión alostéricas.
Síntesis y caracterización de pequeñas moléculas dirigidas a bolsas alostéricas identificadas, centradas en FBW7.
Análisis biofísicos y estructurales (por ejemplo, cristalografía de rayos X) para confirmar las interacciones de unión.
Ensayos funcionales basados en células para evaluar el impacto de las moléculas pequeñas en las vías de degradación de las proteínas (por ejemplo, c-MYC, c-JUN).

Principales resultados:

Un enfoque eficiente identificó oportunidades de unión alostérica significativas en 22 ligasas E3 diversas.
Se descubrieron los primeros enlaces potentes y reversibles de moléculas pequeñas dirigidos a un bolsillo alostérico en FBW7.
Estos aglutinantes de FBW7 fueron confirmados mediante estudios biofísicos y estructurales.
Los ensayos funcionales demostraron que algunos moduladores mejoran la degradación dependiente de FBW7 de c-MYC y c-JUN.

Conclusiones:

Los bolsillos alostéricos representan un recurso en gran medida sin explotar para dirigirse a las ligasas E3 con moléculas pequeñas.
Los moduladores FBW7 alostéricos descubiertos ofrecen un nuevo mecanismo de acción dentro del campo de la TPD.
Estas moléculas sirven como manijas potenciales para el desarrollo de nuevos PROTAC (Chimeras de Orientación a la Proteólisis) y otras terapias de TPD.

Palabras clave:

Allosterismo Las ligasas E3 Ligadabilidad/drogabilidad descubrimiento de fármacos degradación proteica dirigida

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