Discovery of HC-7366: An Orally Bioavailable and Efficacious GCN2 Kinase Activator.
J Med Chem
; 67(7): 5259-5271, 2024 Apr 11.
Article
em En
| MEDLINE
| ID: mdl-38530741
ABSTRACT
A series of activators of GCN2 (general control nonderepressible 2) kinase have been developed, leading to HC-7366, which has entered the clinic as an antitumor therapy. Optimization resulted in improved permeability compared to that of the original indazole hinge binding scaffold, while maintaining potency at GCN2 and selectivity over PERK (protein kinase RNA-like endoplasmic reticulum kinase). The improved ADME properties of this series led to robust in vivo compound exposure in both rats and mice, allowing HC-7366 to be dosed in xenograft models, demonstrating that activation of the GCN2 pathway by this compound leads to tumor growth inhibition.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Proteínas Serina-Treonina Quinases
/
EIF-2 Quinase
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
/
J. med. chem
/
Journal of medicinal chemistry
Assunto da revista:
QUIMICA
Ano de publicação:
2024
Tipo de documento:
Article