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Desarrollo de inhibidores de NRAS G12D basado en un núcleo de 5-azaindol, guiado por la estructura

Joshua B Cox¹, Vinay Nair¹, Pijus Mandal¹

¹Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, 1881 East Road, Houston, Texas 77054, United States.

ACS medicinal chemistry letters

|February 18, 2026

Resumen

Los investigadores desarrollaron IACS-56676, una terapia dirigida para mutaciones de NRAS G12D que se encuentran en cánceres como el melanoma. Este inhibidor selectivo ofrece una nueva herramienta para estudiar la biología de NRAS y el tratamiento del cáncer.

Área de la Ciencia:

Oncología
Biología Molecular
Descubrimiento de Fármacos

Sus antecedentes:

Las mutaciones de NRAS G12D impulsan las neoplasias malignas de melanoma y hematológicas.
Las terapias dirigidas para NRAS G12D son actualmente limitadas, lo que representa una necesidad clínica no satisfecha.

Objetivo del estudio:

Describir el desarrollo guiado por la estructura de IACS-56676, un nuevo inhibidor de NRAS G12D.
Establecer IACS-56676 como un compuesto herramienta para la investigación de la biología de NRAS.
Obtener información sobre cómo lograr la selectividad entre las proteínas NRAS y KRAS.

Principales métodos:

Se emplearon principios de diseño de fármacos guiados por la estructura.
Optimización iterativa de compuestos líderes para mejorar la potencia y la selectividad.
Ensayos bioquímicos para evaluar la actividad del inhibidor frente a variantes de NRAS y KRAS.

Principales resultados:

IACS-56676 se identificó como un inhibidor selectivo y potente de NRAS G12D.
Modificaciones estructurales clave, incluida la estabilización del bucle p y la sustitución de Leu 95, fueron cruciales para la actividad.
El inhibidor demostró selectividad frente a KRAS de tipo salvaje y variantes no respondedoras.

Conclusiones:

IACS-56676 representa un avance significativo en la orientación de las mutaciones de NRAS G12D.
El compuesto sirve como una herramienta valiosa para una mayor investigación de la oncogénesis impulsada por NRAS.
El estudio proporciona un marco para el desarrollo de inhibidores selectivos de RAS.

Palabras clave:

mutante G12D inhibidor de KRAS NRAS SBDD medicina de precisión diseño de fármacos basado en la estructura terapia dirigida

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