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Un inhibidor de doble sitio de CBP/p300 KIX es un modulador selectivo y eficaz de Myb
Stephen T Joy1, Madeleine J Henley1,2, Samantha N De Salle1,2
1Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, United States.
Journal of the American Chemical Society
|September 7, 2021
Resumen
Los investigadores desarrollaron MybLL-tide, un potente inhibidor de doble sitio dirigido a la interacción Myb-CBP / p300 KIX crucial en la leucemia mieloide aguda (AML) y otros cánceres.
Área de la Ciencia:
- La bioquímica
- Biología molecular
- Investigación del cáncer
Sus antecedentes:
- La interacción entre el motivo KIX de la CBP/ p300 y el activador transcripcional Myb está implicada en ciertas leucemias mieloides agudas (LMA) y otros cánceres.
- El dominio CBP / p300 KIX presenta un objetivo desafiante para los inhibidores de moléculas pequeñas debido a sus múltiples sitios de unión, similitudes estructurales con otros dominios, numerosos socios de unión y flexibilidad conformacional.
Objetivo del estudio:
- Desarrollar un inhibidor de moléculas pequeñas altamente específico y potente dirigido a la interacción Myb-CBP/p300 KIX.
- Investigar la eficacia del inhibidor desarrollado en el bloqueo de la expresión génica impulsada por Myb en las células de LMA.
Principales métodos:
- Diseño y síntesis de un inhibidor picomólico de doble sitio, MybLL-tide.
- Perfiles de afinidad y selectividad de MybLL-tide con respecto al dominio CBP/p300 KIX y otros dominios de coactivador.
- Evaluación de la capacidad de MybLL-tide para inhibir la expresión génica dependiente de Myb·KIX en células de LMA en el contexto proteómico.
Principales resultados:
- MybLL-tide demostró una afinidad picomol para el dominio CBP/ p300 KIX, significativamente mayor que los compuestos reportados anteriormente.
- El inhibidor exhibió una selectividad excepcional, con una preferencia de 5.600 veces para el dominio CBP/ p300 KIX sobre otros dominios coactivadores.
- MybLL-tide bloqueó efectivamente la asociación de CBP y p300 con Myb en las células, lo que condujo a la inhibición de genes clave dependientes de Myb·KIX en las células de LMA.
Conclusiones:
- MybLL-tide es una herramienta altamente efectiva y modificable para apuntar selectivamente al dominio CBP/p300 KIX.
- Este inhibidor puede utilizarse para evaluar los efectos de transcripción en las células de LMA y potencialmente en otros cánceres con actividad aberrante de Myb.
- La estrategia de inhibición de doble sitio es prometedora para dirigirse a otros dominios de coactivador desafiantes con múltiples superficies de unión.
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