Identification of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of Met kinase.
Bioorg Med Chem Lett
; 18(6): 1945-51, 2008 Mar 15.
Article
em En
| MEDLINE
| ID: mdl-18289854
ABSTRACT
An amide library derived from the pyrrolo[2,1-f][1,2,4]triazine scaffold led to the identification of modest inhibitors of Met kinase activity. Introduction of polar side chains at C-6 of the pyrrolotriazine core provided significant improvements in in vitro potency. The amide moiety could be replaced with acylurea and malonamide substituents to give compounds with improved potency in the Met-driven GTL-16 human gastric carcinoma cell line. Acylurea pyrrolotriazines with substitution at C-5 demonstrated single digit nanomolar kinase activity. X-ray crystallography revealed that the C-5 substituted pyrrolotriazines bind to the Met kinase domain in an ATP-competitive manner.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirróis
/
Neoplasias Gástricas
/
Triazinas
/
Proteínas Proto-Oncogênicas
/
Receptores de Fatores de Crescimento
/
Receptores Proteína Tirosina Quinases
/
Inibidores Enzimáticos
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Estados Unidos