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Desarrollo de UM-203, un antagonista reversible covalente de STING

Leonard Barasa^1,2, Leo DeOrsey^1,2, Maeve D O'Reilly^1,2

¹Program in Chemical Biology, University of Massachusetts Chan Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, United States.

ACS medicinal chemistry letters

|January 14, 2026

Resumen

Los investigadores desarrollaron UM-203, un nuevo inhibidor covalente reversible que se dirige a la vía de la proteína 2,3-sintasa de monofosfato de guanosina cíclica (cGAS)-estimuladora de genes de interferón (STING). Este compuesto inhibe eficazmente la señalización de STING en sistemas humanos y de ratón, ofreciendo potencial para terapias de enfermedades autoinmunes.

Área de la Ciencia:

Inmunología
Biología Molecular
Descubrimiento de Fármacos

Sus antecedentes:

La vía cGAS-STING es crucial para la inmunidad innata al detectar ADN citosólico e iniciar respuestas inflamatorias.
La desregulación de la vía cGAS-STING está implicada en diversas enfermedades inflamatorias y autoinmunes.
STING es un objetivo terapéutico significativo para el manejo de estas afecciones.

Objetivo del estudio:

Desarrollar y caracterizar un nuevo inhibidor covalente reversible de la vía STING.
Evaluar la eficacia del inhibidor contra la señalización de STING humana y de ratón.
Evaluar el potencial del inhibidor como andamio terapéutico para enfermedades relacionadas con STING.

Principales métodos:

Desarrollo de un inhibidor covalente reversible, UM-203, utilizando una ojiva de alquino-tiazol.
Prueba de la actividad inhibidora de UM-203 en sistemas celulares murinos y humanos.
Evaluación de la eficacia de UM-203 contra la variante común de STING humana (R232) y en monocitos humanos primarios.

Principales resultados:

UM-203 demostró una potente inhibición de la señalización dependiente de STING en modelos de ratón y humanos.
El inhibidor conservó la actividad contra la variante humana prevalente de STING R232.
UM-203 suprimió eficazmente la señalización de STING en monocitos primarios humanos CD14+ y mostró una estabilidad metabólica moderada.

Conclusiones:

UM-203 representa el primer inhibidor covalente reversible de STING desarrollado.
El compuesto muestra promesa como andamio terapéutico para el tratamiento de enfermedades inflamatorias y autoinmunes impulsadas por STING.
El desarrollo adicional de UM-203 podría conducir a nuevos tratamientos para afecciones asociadas con la activación aberrante de STING.

Palabras clave:

Citocinas Oligomerización Estimulador de genes de interferón TBK1 Interferón de tipo I inhibidor

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