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Selective platelet-derived growth factor receptor kinase blockers reverse sis-transformation

Kovalenko, Marina; Gazit, Aviv; Böhmer, A; Rorsman, Charlotte; Rönnstrand, Lars LU ; Heldin, Carl-Henrik; Waltenberger, Johannes; Böhmer, Frank D. and Levitzki, A (1994) In Cancer Research 54(23). p.6106-6114
Abstract
A novel class of tyrosine kinase blockers represented by the tyrphostins AG1295 and AG1296 is described. These compounds inhibit selectively the platelet-derived growth factor (PDGF) receptor kinase and the PDGF-dependent DNA synthesis in Swiss 3T3 cells and in porcine aorta endothelial cells with 50% inhibitory concentrations below 5 and 1 microM, respectively. The PDGF receptor blockers have not effect on epidermal growth factor receptor autophosphorylation; weak effects on DNA synthesis stimulated by insulin, by epidermal growth factor, or by a combination of both; and over an order of magnitude weaker blocking effect on fibroblast growth factor-dependent DNA synthesis. AG1296 potently inhibits signaling of human PDGF alpha- and... (More)
A novel class of tyrosine kinase blockers represented by the tyrphostins AG1295 and AG1296 is described. These compounds inhibit selectively the platelet-derived growth factor (PDGF) receptor kinase and the PDGF-dependent DNA synthesis in Swiss 3T3 cells and in porcine aorta endothelial cells with 50% inhibitory concentrations below 5 and 1 microM, respectively. The PDGF receptor blockers have not effect on epidermal growth factor receptor autophosphorylation; weak effects on DNA synthesis stimulated by insulin, by epidermal growth factor, or by a combination of both; and over an order of magnitude weaker blocking effect on fibroblast growth factor-dependent DNA synthesis. AG1296 potently inhibits signaling of human PDGF alpha- and beta-receptors as well as of the related stem cell factor receptor (c-Kit) but has no effect on autophosphorylation of the vascular endothelial growth factor receptor KDR or on DNA synthesis induced by vascular endothelial growth factor in porcine aortic endothelial cells. Treatment by AG1296 reverses the transformed phenotype of sis-transfected NIH 3T3 cells but has no effect on src-transformed NIH 3T3 cells or on the activity of the kinase p60c-src(F527) immunoprecipitated from these cells. These potent and selective compounds represent leads for the development of novel agents to combat tumors driven by PDGF or to inhibit PDGF action in other diseases in which PDGF plays a key role, such as restenosis. (Less)
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@article{9b0b8d0d-268f-44b1-974d-a64c705ace53,
  abstract     = {A novel class of tyrosine kinase blockers represented by the tyrphostins AG1295 and AG1296 is described. These compounds inhibit selectively the platelet-derived growth factor (PDGF) receptor kinase and the PDGF-dependent DNA synthesis in Swiss 3T3 cells and in porcine aorta endothelial cells with 50% inhibitory concentrations below 5 and 1 microM, respectively. The PDGF receptor blockers have not effect on epidermal growth factor receptor autophosphorylation; weak effects on DNA synthesis stimulated by insulin, by epidermal growth factor, or by a combination of both; and over an order of magnitude weaker blocking effect on fibroblast growth factor-dependent DNA synthesis. AG1296 potently inhibits signaling of human PDGF alpha- and beta-receptors as well as of the related stem cell factor receptor (c-Kit) but has no effect on autophosphorylation of the vascular endothelial growth factor receptor KDR or on DNA synthesis induced by vascular endothelial growth factor in porcine aortic endothelial cells. Treatment by AG1296 reverses the transformed phenotype of sis-transfected NIH 3T3 cells but has no effect on src-transformed NIH 3T3 cells or on the activity of the kinase p60c-src(F527) immunoprecipitated from these cells. These potent and selective compounds represent leads for the development of novel agents to combat tumors driven by PDGF or to inhibit PDGF action in other diseases in which PDGF plays a key role, such as restenosis.},
  author       = {Kovalenko, Marina and Gazit, Aviv and Böhmer, A and Rorsman, Charlotte and Rönnstrand, Lars and Heldin, Carl-Henrik and Waltenberger, Johannes and Böhmer, Frank D. and Levitzki, A},
  issn         = {1538-7445},
  keyword      = {Epidermal Growth Factor/antagonists & inhibitors
Receptors,3T3 Cells
Animals
Antineoplastic Agents/*pharmacology
Catechols/*pharmacology
Cell Division/drug effects
Cell Transformation,Neoplastic/*drug effects
DNA/biosynthesis
Mice
Nitriles/*pharmacology
Phosphorylation
Platelet-Derived Growth Factor/pharmacology
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-sis
Receptor Protein-Tyrosine Kinases/*antagonists & inhibitors
Receptor,Platelet-Derived Growth Factor/*metabolism
*Tyrphostins},
  language     = {eng},
  number       = {23},
  pages        = {6106--6114},
  publisher    = {American Association for Cancer Research Inc.},
  series       = {Cancer Research},
  title        = {Selective platelet-derived growth factor receptor kinase blockers reverse sis-transformation},
  volume       = {54},
  year         = {1994},
}