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La proteólisis puente dirigida a la quimera (PROTAC) permite la degradación de objetivos no farmacológicos

Yan Xiong¹, Yue Zhong¹, Hyerin Yim¹

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

Journal of the American Chemical Society

|November 30, 2022

Resumen

Una nueva estrategia de Proteólisis Dirigida a la Quimera (PROTAC) permite la degradación de proteínas previamente no farmacológicas. Este enfoque degradó con éxito la ciclina D1, una proteína que carece de enlaces de moléculas pequeñas, ofreciendo una nueva vía terapéutica.

Área de la Ciencia:

La bioquímica
Biología molecular
Descubrimiento de drogas

Sus antecedentes:

Las quimeras dirigidas a la proteólisis (PROTAC) son terapias emergentes para la degradación dirigida de las proteínas.
Los PROTAC actuales se limitan a las proteínas con enlaces de moléculas pequeñas disponibles, excluyendo muchos objetivos "indruggables".
La ciclina D1 es un regulador clave del ciclo celular implicado en el cáncer, pero carece de enlaces de moléculas pequeñas.

Objetivo del estudio:

Introducir una estrategia novedosa de "puente PROTAC" dirigida a las proteínas que carecen de enlaces de moléculas pequeñas.
Desarrollar el primer degradador de su clase para la ciclina D1 utilizando este nuevo enfoque.
Evaluar la eficacia de la estrategia puente PROTAC y del degradante desarrollado en las células cancerosas.

Principales métodos:

Desarrollo de un PROTAC puente mediante el enlace de un ligando asociado de unión a la ciclina D1 con un ligando de la E3 ligasa.
Utilizando la ligasa E3 de von Hippel-Lindau (VHL) para la degradación dirigida de las proteínas.
Evaluación de la degradación de la ciclina D1 y su impacto en la proliferación de células cancerosas.

Principales resultados:

Desarrollo exitoso de MS28, un PROTAC puente dirigido al complejo CDK4/6-ciclina D1.
MS28 demostró una degradación eficiente y rápida de la ciclina D1, superando el rendimiento de los inhibidores CDK4/ 6 existentes.
MS28 suprimió significativamente la proliferación de células cancerosas con mayor eficacia que los inhibidores y degradantes de la CDK4/ 6.

Conclusiones:

La estrategia PROTAC puente ofrece una plataforma versátil para apuntar a proteínas previamente no farmacológicas.
MS28 representa un nuevo agente terapéutico dirigido a la ciclina D1 y es prometedor en el tratamiento del cáncer.
Este enfoque amplía el alcance de la tecnología PROTAC para el descubrimiento y desarrollo de fármacos.

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