Inhibition of basic fibroblast growth factor-mediated tyrosine phosphorylation and protein synthesis by PD 145709, a member of the 2-thioindole class of tyrosine kinase inhibitors.
PD 145709, which represents one member of a new structural class of tyrosine kinase inhibitors, the thioindoles, inhibited basic fibroblast growth factor (bFGF)-mediated tyrosine phosphorylation in Swiss 3T3 murine fibroblasts. Half-maximal suppression was attained when cells were exposed for 2 h to 4.5 microM. Little or no inhibition of epidermal growth factor (EGF)- or platelet-derived growth factor (PDGF)-mediated tyrosine phosphorylation was observed at concentrations as high as 50 microM. The inhibition of bFGF-mediated phosphorylation occurred rapidly with maximal effects occurring after the cells were exposed to PD 145709 for 90 min. Once established, the inhibition was irreversible and remained for at least 2 h after PD 145709 was removed from the extracellular medium. PD 145709 also inhibited bFGF-mediated phosphorylation as well as FGF receptor autophosphorylation in a human breast carcinoma, MDA-MB-134, which overexpresses the FGF1 receptor. PD 145709 caused an increase of c-jun mRNA in response to EGF, PDGF, bFGF and serum. This effect may be due to the fact that this compound was a potent inhibitor of protein synthesis in cells and may cause superinduction of growth factor-mediated gene expression similar to other inhibitors of protein synthesis. Inhibition of protein synthesis occurred in fibroblasts exposed to PD 145709 with half-maximal inhibition at 0.5 microM, but not in an in vitro translation system at concentrations as high as 20 microM. This indicates that an intact viable cell is necessary for inhibition to occur and is compatible with a mechanism by which PD 145709 interferes with signals or protein factors that are involved with the initiation or protein synthesis.
Fry
D W
DW
Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
Nelson
J M
JM
D016475:3T3 Cells; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D016758:Genes, jun; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012313:RNA / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism*
D007211:Indoles; C098225:PD 145709; D011500:Protein Synthesis Inhibitors; D016222:Fibroblast Growth Factor 2; D014443:Tyrosine; D012313:RNA; D004247:DNA; D011505:Protein-Tyrosine Kinases