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Inhibición directa del complejo del factor de transcripción NOTCH
Raymond E Moellering1, Melanie Cornejo, Tina N Davis
1Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Nature
|November 13, 2009
Resumen
Los investigadores desarrollaron un nuevo inhibidor de péptidos, SAHM1, que bloquea efectivamente el complejo de transactivación NOTCH. Este enfoque dirigido es prometedor para el tratamiento de cánceres impulsados por NOTCH como la leucemia linfoblástica aguda de células T (T-ALL).
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Descubrimiento de Drogas Descubrimiento de Drogas
- Investigación del cáncer Investigación del cáncer.
Sus antecedentes:
- Dirigirse a los complejos de factores de transcripción para el descubrimiento de ligandos es un desafío debido a su falta de sitios de unión adecuados para moléculas pequeñas.
- La vía de señalización NOTCH juega un papel crítico en la diferenciación celular y con frecuencia está desregulada en varios tipos de cáncer, incluida la leucemia linfoblástica aguda de células T (T-ALL).
Objetivo del estudio:
- Diseñar y validar un péptido sintético capaz de inhibir directamente el complejo de transactivación NOTCH.
- Evaluar el potencial terapéutico de este péptido en modelos preclínicos de tumores malignos impulsados por NOTCH.
Principales métodos:
- Diseño de péptidos alfa helicoidales estabilizados y permeables a las células que se dirigen al complejo de transactivación NOTCH.
- Caracterización in vitro de la afinidad de unión de péptidos y su efecto en el ensamblaje complejo.
- Evaluación de la eficacia del péptido en la supresión de genes activados por NOTCH e inhibición de la proliferación en células cancerosas y un modelo de ratón de T-ALL.
Principales resultados:
- Se desarrolló un péptido grapado con hidrocarburos, SAHM1, que se une con alta afinidad al complejo de transactivación NOTCH.
- SAHM1 evita efectivamente el ensamblaje del complejo transcripcional activo, lo que lleva a la supresión de genes activados por NOTCH en todo el genoma.
- SAHM1 demostró potentes efectos antiproliferativos específicos de NOTCH tanto en cultivos celulares como en un modelo de ratón de T-ALL.
Conclusiones:
- La inhibición directa del complejo de transactivación NOTCH se puede lograr utilizando péptidos alfa helicoidales estabilizados.
- SAHM1 representa una estrategia terapéutica prometedora para las enfermedades impulsadas por la señalización NOTCH aberrante, particularmente la leucemia linfoblástica aguda de células T.
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