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DCAF11 apoya la degradación de proteínas dirigida por quimeras dirigidas a la proteólisis electrofílica

Xiaoyu Zhang¹, Lena M Luukkonen², Christie L Eissler²

¹The Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92307, United States.

Journal of the American Chemical Society

|March 30, 2021

Resumen

Las nuevas quimeras electrofílicas dirigidas a la proteólisis (PROTAC) se dirigen a DCAF11, una ligasa E3 no caracterizada anteriormente. Este descubrimiento amplía el conjunto de herramientas para la degradación dirigida de proteínas en células humanas, incluidas las terapias contra el cáncer.

Área de la Ciencia:

Biología molecular
La bioquímica
Biología Química

Sus antecedentes:

La degradación de proteínas inducida por ligandos utiliza el sistema ubiquitina-proteasoma para la eliminación dirigida de proteínas.
Se sabe que un número limitado de ligasas E3 apoyan este proceso, lo que dificulta el desarrollo de quimeras dirigidas a la proteólisis (PROTAC).
Se necesitan nuevas ligasas y compuestos E3 para el diseño eficaz de PROTAC.

Objetivo del estudio:

Descubrir nuevas ligasas E3 que puedan apoyar la degradación de proteínas inducida por ligandos utilizando PROTACs electrófilos.
Identificar compuestos bifuncionales capaces de comprometer covalentemente a las ligasas E3 para la eliminación específica de proteínas.
Caracterizar el mecanismo de acción y el alcance del sustrato de las interacciones E3 ligasa-PROTAC recién identificadas.

Principales métodos:

Evaluación funcional de una biblioteca enfocada de PROTAC electrofílicos candidatos.
Estudios mecánicos que incluyen la modificación covalente de residuos específicos de cisteína en las ligasas E3.
Pruebas de degradación de proteínas endógenas en células humanas de cáncer de próstata.

Principales resultados:

Descubrimiento de PROTACs electrófilos que involucran covalentemente a DCAF11, un adaptador de sustrato de ligasa E3 mal caracterizado.
Demostrar que DCAF11 media la degradación de las proteínas inducida por ligandos mediante la modificación de cisteínas específicas.
La degradación exitosa de las proteínas endógenas, incluyendo FBKP12 y el receptor de andrógenos, en las células de cáncer de próstata utilizando PROTACs que reclutan DCAF11.

Conclusiones:

DCAF11 se identifica como una nueva ligasa E3 capaz de apoyar la degradación de proteínas inducida por ligandos.
Los PROTAC electrofílicos proporcionan una estrategia viable para involucrar y explotar DCAF11 para la eliminación de proteínas dirigidas.
Este trabajo amplía el repertorio de ligasas E3 para el desarrollo de PROTAC y ofrece posibles vías terapéuticas en el cáncer.

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