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Una estrategia quimioproteómica para la identificación directa y proteomática del sitio objetivo del inhibidor
Christopher M Browne1,2, Baishan Jiang1,2, Scott B Ficarro1,2,3
1Department of Cancer Biology , Dana-Farber Cancer Institute , Boston , Massachusetts 02215 , United States.
Journal of the American Chemical Society
|December 7, 2018
Resumen
Un nuevo método quimioproteómico, CITe-Id, mapea con precisión los sitios de unión de fármacos covalentes en las proteínas. Este enfoque identificó nuevos objetivos para el desarrollo de fármacos, incluida la quinasa PKN3 insuficientemente estudiada, lo que condujo a un nuevo inhibidor selectivo.
Área de la Ciencia:
- Proteomía
- Biología Química
- Descubrimiento de drogas
Sus antecedentes:
- Los medicamentos covalentes ofrecen ventajas terapéuticas pero se enfrentan a riesgos de toxicidad debido a la modificación de la cisteína fuera del objetivo.
- Los métodos actuales carecen de una cuantificación directa a nivel de aminoácidos de la unión del inhibidor covalente a través del proteoma.
Objetivo del estudio:
- Desarrollar un nuevo enfoque quimioproteómico, CITe-Id, para el mapeo preciso de las interacciones farmacológicas covalentes.
- Caracterizar la selectividad de los inhibidores covalentes en todo el proteoma e identificar nuevos objetivos farmacológicos.
Principales métodos:
- Desarrollo de CITe-Id, una plataforma quimioproteómica que utiliza inhibidores covalentes como reactivos de enriquecimiento.
- Análisis cuantitativo de la modificación cisteína-tiol dependiente de la dosis en todo el proteoma.
- Aplicación de CITe-Id para el estudio del inhibidor irreversible de la CDK THZ1.
Principales resultados:
- CITe-Id permitió la cuantificación directa de la modificación de la cisteína dependiente de la dosis por inhibidores covalentes.
- El análisis de THZ1 reveló objetivos de quinasa inesperados, incluida una nueva cisteína en PKN3 (C840).
- Esto condujo al desarrollo de JZ128, un inhibidor selectivo covalente de PKN3, y la identificación de sus sustratos.
Conclusiones:
- CITe-Id es una herramienta poderosa para caracterizar la selectividad del inhibidor covalente e identificar nuevas cisteínas farmacodinámicas.
- El método informa el diseño de fármacos basado en la estructura y acelera el desarrollo de terapias covalentes dirigidas.
- Este trabajo proporciona nuevos conocimientos sobre la biología de PKN3 y su potencial como objetivo farmacológico.
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