Inhibition of the Abl Protein-Tyrosine Kinase in Vitro and in Vivo by a 2-Phenylaminopyrimidine Derivative

摘要: Oncogenic activation of Abl proteins due to structural modifications can occur as a result viral transduction or chromosomal translocation. The tyrosine protein kinase activity oncogenic is known be essential for their transforming activity. Therefore, we have attempted identify selective inhibitors the kinase. Herein describe an inhibitor (CGP 57148) and platelet-derived growth factor (PDGF) receptor protein-tyrosine kinases from 2-phenylaminopyrimidine class, which highly active in vitro vivo. Submicromolar concentrations compound inhibited both v-Abl PDGF autophosphorylation PDGF-induced c-fos mRNA expression selectively intact cells. In contrast, ligand-induced response epidermal (EGF), insulin-like factor-I, insulin showed no weak inhibition by high CGP 57148. induced EGF, fibroblast factor, phorbol ester was also insensitive antiproliferative assays, more than 30-100-fold potent inhibiting v-abl-transformed PB-3c cells v-sis-transformed BALB/c 3T3 relative EGF-dependent BALB/MK cells, interleukin-3-dependent FDC-P1 T24 bladder carcinoma line. Furthermore, anchorage-independent v-abl- potently When tested vivo, 57148 antitumor at tolerated doses against tumorigenic had when using src-transformed These findings suggest that may therapeutic potential treatment diseases involve abnormal cellular proliferation deregulation activation.