Estructuras del dominio de la tirosina quinasa del receptor del factor de crecimiento de los fibroblastos en complejo con inhibidores
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Published on: January 6, 2017
M Mohammadi1, G McMahon, L Sun
1Department of Pharmacology, New York University Medical Center, New York, NY 10016, USA.
Science (New York, N.Y.)
|May 9, 1997
Resumen
Los investigadores descubrieron nuevos inhibidores basados en oxindoles dirigidos a la actividad de la quinasa del receptor 1 del factor de crecimiento de los fibroblastos (FGFR1). El análisis estructural revela mecanismos de unión cruciales para el desarrollo de nuevas terapias contra el cáncer dirigidas a las tirosinacinasas.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Química medicinal Química medicinal es el campo de la química medicinal.
- Biología Estructural Biología estructural.
Sus antecedentes:
- Las proteínas tirosina quinasas (PTK) son cruciales en la señalización celular e implicadas en varias enfermedades, incluido el cáncer.
- El receptor 1 del factor de crecimiento de los fibroblastos (FGFR1) es una PTK clave involucrada en la proliferación y diferenciación celular.
- Dirigirse a la actividad aberrante de PTK es una estrategia significativa en la terapia del cáncer.
Objetivo del estudio:
- Identificar y caracterizar nuevos inhibidores de la actividad de PTK.
- Investigar los efectos inhibidores y la especificidad de los compuestos basados en oxindoles contra el FGFR1.1.
- Aclarar las bases estructurales de la inhibición para el diseño racional de fármacos.
Principales métodos:
- Síntesis y detección de una nueva clase de compuestos basados en oxindoles.
- Ensayos bioquímicos para medir la inhibición de la quinasa de FGFR1 y otras receptoras de las tirosinacinasas.
- Cristalografía de rayos X para determinar las estructuras de FGFR1 en complejo con inhibidores.
Principales resultados:
- Identificación de una nueva clase de inhibidores de la proteína tirosina quinasa de la indolinona (núcleo de oxindole).
- Dos compuestos demostraron una potente inhibición de la actividad de la quinasa del receptor del factor de crecimiento de los fibroblastos 1 (FGFR1).
- Las estructuras cristalinas revelaron la unión de oxindole al sitio del ATP y las interacciones con los residuos de la región de la bisagra, con un inhibidor que induce cambios conformacionales.
Conclusiones:
- Los compuestos basados en oxindoles representan una clase prometedora de inhibidores de FGFR1.
- Las ideas estructurales proporcionan una base para diseñar inhibidores de la quinasa más específicos y potentes.
- Estos hallazgos apoyan el desarrollo de nuevas terapias para los cánceres impulsados por la señalización aberrante de la tirosina quinasa.
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