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Descubrimiento y optimización de ligandos de pequeñas moléculas para los bromodomaines CBP/p300

Duncan A Hay¹, Oleg Fedorov, Sarah Martin

¹Department of Chemistry, University of Oxford , South Parks Road, Oxford OX1 3TA, U.K.

Journal of the American Chemical Society

|June 20, 2014

Resumen

Los investigadores desarrollaron potentes y selectivos inhibidores de pequeñas moléculas dirigidos a los bromodomaines CBP/p300. Estos nuevos ligandos son prometedores para el estudio de las funciones de la CBP/p300 y su validación como dianas terapéuticas.

Área de la Ciencia:

Química Medicinal Química medicinal es el campo de la química medicinal.
Biología Química Biología química.
La epigenética es la epigenética.

Sus antecedentes:

Los inhibidores de moléculas pequeñas para los bromodomaines más allá de la familia BET son escasos.
CBP / p300 son reguladores epigenéticos clave con un potencial terapéutico poco explorado.

Objetivo del estudio:

Diseñar y sintetizar inhibidores potentes y selectivos dirigidos al bromodomaín CBP/p300.
Investigar y optimizar la selectividad contra los bromodomaines relacionados, en particular los miembros de la familia BET.

Principales métodos:

Diseño de fármacos basado en fragmentos y síntesis paralela.
Acoplamientos Suzuki, formación de benzimidazol y aminación reductora.
Ensayos de estabilidad térmica, cristalografía de rayos X, FRAP y ensayos de reportero.

Principales resultados:

Derivados optimizados de 5-isoxazolyl-benzimidazol con afinidad nanomolar para CBP/p300.
Se logró una selectividad de 40 veces para CBP sobre BRD4 ((1) a través del diseño guiado por la estructura.
Actividad celular demostrada y bromodomaínas CBP/p300 validadas como objetivos farmacológicos.

Conclusiones:

Desarrolló inhibidores de la bromodomaína CBP/p300 altamente potentes y selectivos.
Estos compuestos son herramientas valiosas para la investigación epigenética y el descubrimiento de fármacos.
Validación de los bromodomaínos CBP/p300 como objetivos terapéuticos prometedores.

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