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Descubrimiento de moduladores de moléculas pequeñas de la vía de Sonic Hedgehog
Giannina I Schaefer1, José R Perez, Jeremy R Duvall
1Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
Journal of the American Chemical Society
|June 4, 2013
Resumen
Los investigadores descubrieron dos nuevos inhibidores de moléculas pequeñas, BRD50837 y BRD9526, dirigidos a la vía de señalización Sonic Hedgehog (Shh). Estos compuestos ofrecen nuevos mecanismos para estudiar la regulación de la vía SHH y su papel en enfermedades como el cáncer.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- Química Medicinal La Química Medicinal es un campo de estudio de la química medicinal.
Sus antecedentes:
- La vía de señalización del erizo es crucial para el desarrollo embrionario y la homeostasis tisular.
- La desregulación de la vía del erizo está implicada en varios tipos de cáncer y trastornos del desarrollo.
- La comprensión molecular actual de la vía del erizo es limitada, lo que requiere nuevas herramientas de investigación.
Objetivo del estudio:
- Descubrir y caracterizar nuevos inhibidores de moléculas pequeñas de la vía Sonic Hedgehog (Shh).
- Explorar las relaciones estructura-actividad y los mecanismos de acción de estos nuevos inhibidores.
- Para proporcionar valiosas sondas químicas para una mayor investigación de la cascada de señalización Shh.
Principales métodos:
- Síntesis de una biblioteca diversa de pequeñas moléculas, incluidos compuestos definidos estereocímicamente.
- Cribado de la biblioteca para identificar potentes inhibidores de la vía Shh.
- Estudios mecanicistas detallados para aclarar el modo de acción de los inhibidores identificados.
Principales resultados:
- Identificación de dos potentes inhibidores de la vía Shh: BRD50837 y BRD9526.
- Demostración de las relaciones estructura-actividad dependientes de la estereoquímica para ambos compuestos.
- Caracterización de nuevos mecanismos de acción distintos de los inhibidores existentes como la ciclopamina.
Conclusiones:
- BRD50837 y BRD9526 representan nuevas herramientas valiosas para diseccionar las complejidades de la vía de señalización Shh.
- Los distintos mecanismos de estos inhibidores ofrecen nuevas vías para la orientación terapéutica de las enfermedades relacionadas con Shh.
- Investigaciones adicionales que utilicen estas sondas avanzarán en nuestra comprensión de la regulación de la vía y su papel en la enfermedad.
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