RESUMO
The insulin-like growth factor-1 receptor (IGF-1R) plays an important role in the regulation of cell growth and differentiation, and in protection from apoptosis. IGF-1R has been shown to be an appealing target for the treatment of human cancer. Herein, we report the synthesis, structure-activity relationships (SAR), X-ray cocrystal structure and in vivo tumor study results for a series of 2,4-bis-arylamino-1,3-pyrimidines.
Assuntos
Inibidores de Proteínas Quinases/química , Pirimidinas/química , Quinolinas/síntese química , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Sítios de Ligação , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Humanos , Camundongos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Quinolinas/química , Quinolinas/farmacocinética , Receptor IGF Tipo 1/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
N-3-(Phenylcarbamoyl)arylpyrimidine-5-carboxamides are a novel class of selective Lck inhibitors. This series of compounds derives its selectivity from a hydrogen bond with the gatekeeper Thr316 of the enzyme. X-ray co-crystal structural data, structure-activity relationships, and the synthesis of these inhibitors are reported herein.