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Diseño basado en la bioinformática estructural de inhibidores selectivos e irreversibles de la quinasa

Michael S Cohen¹, Chao Zhang, Kevan M Shokat

¹Program in Chemistry and Chemical Biology, and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143-2280, USA.

Science (New York, N.Y.)

|May 28, 2005

Resumen

El diseño de inhibidores selectivos de la quinasa es un desafío debido a los sitios activos conservados. Los investigadores identificaron dos aminoácidos clave en la proteína ribosomal p90 S6 quinasa (RSK) que permiten el diseño de inhibidores potentes y selectivos.

Área de la Ciencia:

La bioquímica es la bioquímica.
Biología Estructural Biología estructural.
Farmacología Farmacología.

Sus antecedentes:

Los sitios activos de la proteína quinasa están altamente conservados en 491 dominios humanos.
El diseño de inhibidores selectivos para las proteína quinasas presenta un desafío significativo.

Objetivo del estudio:

Identificar las características estructurales que confieren selectividad para la proteína ribosómica p90 S6 quinasa (RSK).
Diseñar y validar un inhibidor selectivo dirigido a RSK.

Principales métodos:

Utilizó un enfoque de bioinformática estructural para analizar los sitios activos de la proteína quinasa.
Diseñó un inhibidor de fluorometilcetona dirigido a los filtros de selectividad de RSK identificados (treonina y cisteína).
Potencia inhibidora y selectividad probadas en células de mamíferos, incluidas las quinasas genéticamente modificadas.

Principales resultados:

Identificó una treonina y una cisteína como filtros de selectividad clave en el sitio activo de RSK.
Desarrolló un inhibidor de la fluorometilcetona que inactivó potentemente y selectivamente RSK1 y RSK2.
Demostró que las quinasas que carecen de uno o ambos filtros eran resistentes, pero se volvieron sensibles al introducir el filtro.

Conclusiones:

Dos aminoácidos específicos (treonina y cisteína) son suficientes para conferir sensibilidad del inhibidor a la RSK.
Este hallazgo proporciona una base para el desarrollo de inhibidores de la quinasa altamente selectivos.

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