ABSTRACT
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.
Subject(s)
Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Quinolines/chemical synthesis , Receptor, IGF Type 1/antagonists & inhibitors , Animals , Binding Sites , Crystallography, X-Ray , Drug Evaluation, Preclinical , Humans , Mice , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Quinolines/chemistry , Quinolines/pharmacokinetics , Receptor, IGF Type 1/metabolism , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
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.
