RESUMEN

Wnt signaling pathway plays a critical role in numerous cellular processes, including tumor initiation, proliferation, invasion/infiltration, metastasis formation and resistance to chemotherapy. In a drug discovery project aimed at the identification of inhibitors of the canonical Wnt pathway, we selected a series of quinazoline 2,4-diones as starting point for the therapeutic treatment of glioblastoma multiforme. Despite of poor physico-chemical properties of hit compound 1, our medicinal chemistry effort allowed the discovery and characterization of lead compound 33 (SEN461), with improved ADME profile, good bioavailability and active in vitro and in vivo in glioblastoma, gastric and sarcoma tumors.

Asunto(s)

Antineoplásicos/química , Antineoplásicos/farmacología , Quinazolinas/química , Quinazolinas/farmacología , Vía de Señalización Wnt/efectos de los fármacos , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Quinazolinas/metabolismo , Quinazolinas/farmacocinética , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto