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La inhibición selectiva de las bromodomaínas BET
Panagis Filippakopoulos1, Jun Qi, Sarah Picaud
1Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.
Nature
|September 28, 2010
Resumen
Los investigadores desarrollaron JQ1, una pequeña molécula que inhibe las proteínas lectoras epigenéticas llamadas bromodomaínas. Esta molécula se muestra prometedora en el tratamiento de ciertos tipos de cáncer al dirigirse a la proteína BRD4, ofreciendo una nueva estrategia terapéutica.
Área de la Ciencia:
- La epigenética es la epigenética.
- Biología Química Biología química.
- Biología del cáncer Biología del cáncer.
Sus antecedentes:
- Las proteínas epigenéticas son objetivos clave para el descubrimiento de fármacos, pero han faltado inhibidores para los módulos de unión a la histona (bromodomaínas).
- Los "escritores" y "borradores" epigenéticos han tenido éxito, pero los "lectores" siguen siendo en gran medida no dirigidos.
Objetivo del estudio:
- Identificar y caracterizar los inhibidores de moléculas pequeñas dirigidos a los bromodomaines, una clase de proteínas lectoras epigenéticas.
- Explorar el potencial terapéutico de la inhibición de las interacciones proteína-proteína mediadas por bromodomaína en el cáncer.
Principales métodos:
- Desarrollo de una pequeña molécula permeable a las células, JQ1, dirigida a los motivos de unión de acetil-lisina.
- Determinación de la estructura cocristalina de JQ1 con el miembro de la familia BRD4 de bromodomaínas y extra-terminales (BET).
- Pruebas in vitro e in vivo de JQ1 en líneas celulares de cáncer y modelos de xenotransplante derivados de pacientes.
Principales resultados:
- JQ1 demostró una alta potencia y especificidad para un subconjunto de bromodomaínos humanos, particularmente BRD4.
- Las estructuras cocristalinas revelaron la unión complementaria de JQ1 a la cavidad de acetil-lisina de BRD4.
- El tratamiento con JQ1 condujo a la diferenciación escamosa y a efectos antiproliferativos en los cánceres dependientes de BRD4.
Conclusiones:
- JQ1 representa una prueba de concepto para dirigirse a las interacciones epigenéticas de las proteínas lectoras.
- Los hallazgos establecen un andamio químico versátil para el desarrollo de sondas químicas dirigidas al bromodomain.
- La orientación de BRD4 con JQ1 muestra un potencial terapéutico para carcinomas escamosos específicos e incurables.
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