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Inhibidores covalentes irreversibles basados en 2-etilbenzaldehído dirigidos a las lisinas para las proteínas cinasas
Peng Chen1, Guanghui Tang2, Chengjun Zhu3
1School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China.
Journal of the American Chemical Society
|February 12, 2023
Resumen
Este estudio introduce una nueva estrategia basada en el 2-etilbenzaldehído (EBA) para la creación de inhibidores covalentes irreversibles selectivos dirigidos a la lisina celular. El enfoque generó con éxito potentes inhibidores de ABL quinasa, EGFR y Mcl-1, lo que demuestra una amplia aplicabilidad.
Área de la Ciencia:
- Química medicinal
- Biología Química
- Descubrimiento de drogas
Sus antecedentes:
- Los inhibidores covalentes irreversibles dirigidos a las lisinas están ganando interés, particularmente para la investigación de la quinasa.
- Las composiciones químicas existentes para los inhibidores selectivos de la lisina activa en las células son limitadas.
- La orientación de las lisinas catalíticas conservadas ofrece una ruta hacia la inhibición potente y selectiva.
Objetivo del estudio:
- Desarrollar una nueva estrategia basada en 2-etilbenzaldehído (EBA) para los inhibidores covalentes irreversibles dirigidos a la lisina.
- Para generar inhibidores potentes y selectivos de moléculas pequeñas contra la ABL quinasa.
- Validar la generalidad de la estrategia de la ABE con respecto a otros objetivos como el EGFR y el Mcl-1.
Principales métodos:
- Diseño y síntesis de moléculas pequeñas a base de 2-etilbenzaldehído (EBA).
- Evaluación de la potencia del inhibidor, la selectividad y la actividad celular.
- Evaluación del compromiso covalente con las proteínas diana (ABL, EGFR, Mcl-1) en las células.
- Análisis de los efectos fuera del objetivo y del tiempo de residencia.
Principales resultados:
- Los inhibidores basados en EBA demostraron una inhibición potente y selectiva de la ABL quinasa al dirigirse a su lisina catalítica.
- Los compuestos eran celular-activos, involucrando covalentemente a la kinasa ABL endógena en las células K562 con largos tiempos de residencia.
- La estrategia se generalizó para crear inhibidores de EGFR (kinasa) y Mcl-1 (no kinasa), dirigidos tanto a las lisinas catalíticas como a las no catalíticas.
- Se observó una mínima interacción fuera del objetivo.
Conclusiones:
- La estrategia basada en 2-etilbenzaldehído (EBA) proporciona una plataforma versátil para el desarrollo de inhibidores covalentes irreversibles selectivos dirigidos a la lisina.
- Este enfoque permite la creación de inhibidores potentes y celulares activos contra diversos objetivos biológicos, incluidas las quinasas y las no quinasas.
- Los inhibidores desarrollados exhiben propiedades favorables como el largo tiempo de residencia y la selectividad del objetivo, allanando el camino para nuevas estrategias terapéuticas.
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