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Degradación de proteínas dirigida por PROTACs electrófilos que involucran estereoselectivamente y específicamente el

Yongfeng Tao¹, David Remillard¹, Ekaterina V Vinogradova¹

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

Journal of the American Chemical Society

|September 28, 2022

Resumen

Los investigadores descubrieron nuevos acrilamidos de azetidina que se dirigen a DCAF1 para la degradación de las proteínas. Este avance en la degradación dirigida de proteínas abre nuevas vías para la investigación química y el descubrimiento de fármacos utilizando PROTACs electrófilos.

Área de la Ciencia:

Biología Química
Descubrimiento de drogas
Proteomía

Sus antecedentes:

La degradación proteica dirigida (TPD) utilizando compuestos heterobifuncionales y pegamentos moleculares es una estrategia prometedora para el descubrimiento de fármacos.
Un número limitado de ligasas E3 tiene ligandos de moléculas pequeñas conocidos, lo que dificulta el pleno potencial de la TPD.
El descubrimiento de nuevas ligasas E3 y sus ligandos es crucial para el avance de terapias basadas en TPD.

Objetivo del estudio:

Identificar nuevos ligandos para las ligasas E3 para ampliar el conjunto de herramientas para la degradación proteica dirigida.
Desarrollar nuevas sondas químicas y posibles fármacos candidatos utilizando estrategias de TPD.
Explorar el mecanismo de acción de los nuevos agentes TPD dirigidos a DCAF1.

Principales métodos:

La proteómica química fue empleada para descubrir nuevos ligandos.
Las acrilamidas de azetidina fueron sintetizadas y caracterizadas por su reactividad.
Las quimeras dirigidas a la proteólisis electrofílica (PROTAC) se desarrollaron utilizando ligandos DCAF1.
Se investigó la estereoselectividad y la especificidad del sitio de unión del ligando utilizando líneas celulares mutantes (C1113A).

Principales resultados:

Las acrilamidas de azetidina se identificaron como ligandos covalentes estereoselectivos y específicos del sitio para DCAF1, que reaccionan con la cisteína 1113.
Estos ligandos se desarrollaron con éxito en PROTACs electrófilos que indujeron la degradación proteica dirigida en las células humanas.
Se confirmó que el proceso de degradación es estereoselectivo y depende del residuo C1113 de DCAF1.
Los estudios mecanicistas revelaron que solo es necesaria una baja participación de DCAF1 para la degradación efectiva de las proteínas a través de los PROTAC electrófilos.

Conclusiones:

El análisis proteómico químico de compuestos electrofílicos definidos estereocímicamente puede identificar nuevos sitios ligábeles en las ligasas E3.
Las acrilamidas de azetidina descubiertas para DCAF1 representan una nueva clase de ligandos para la degradación dirigida de proteínas.
Este trabajo amplía las posibilidades para el desarrollo de nuevas sondas químicas y fármacos que utilizan la tecnología electrofílica PROTAC.

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