RESUMEN

Features from a high throughput screening (HTS) hit and a previously reported scaffold were combined to generate 1,7-naphthyridones as novel KDM5 enzyme inhibitors with nanomolar potencies. These molecules exhibited high selectivity over the related KDM4C and KDM2B isoforms. An X-ray co-crystal structure of a representative molecule bound to KDM5A showed that these inhibitors are competitive with the co-substrate (2-oxoglutarate or 2-OG).

Asunto(s)

Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Naftiridinas/farmacología , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Represoras/antagonistas & inhibidores , Proteína 2 de Unión a Retinoblastoma/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Perros , Diseño de Fármacos , Humanos , Células de Riñón Canino Madin Darby , Naftiridinas/química , Relación Estructura-Actividad