RETRACTED: Selective inhibition of the platelet-derived growth factor signal transduction pathway by a protein-tyrosine kinase inhibitor of the 2-phenylaminopyrimidine class.

Abstract

The platelet-derived growth factor (PDGF) receptor is a member of the transmembrane growth factor receptor protein family with intrinsic protein-tyrosine kinase activity. We describe a potent protein-tyrosine kinase inhibitor (CGP 53716) that shows selectivity for the PDGF receptor in vitro and in the cell. The compound shows selectivity for inhibition of PDGF-mediated events such as PDGF receptor autophosphorylation, cellular tyrosine phosphorylation, and c-fos mRNA induction in response to PDGF stimulation of intact cells. In contrast, ligand-induced autophosphorylation of the epidermal growth factor (EGF) receptor, insulin receptor, and the insulin-like growth factor I receptor, as well as c-fos mRNA expression induced by EGF, fibroblast growth factor, and phorbol ester, was insensitive to inhibition by CGP 53716. In antiproliferative assays, the compound was approximately 30-fold more potent in inhibiting PDGF-mediated growth of v-sis-transformed BALB/c 3T3 cells relative to inhibition of EGF-dependent BALB/Mk cells, interleukin-3-dependent FDC-P1 cells, and the T24 bladder carcinoma line. When tested in vivo using highly tumorigenic v-sis- and human c-sis-transformed BALB/c 3T3 cells, CGP 53716 showed antitumor activity at well-tolerated doses. In contrast, CGP 53716 did not show antitumor activity against xenografts of the A431 tumor, which overexpresses the EGF receptor. These findings suggest that CGP 53716 may have therapeutic potential for the treatment of diseases involving abnormal cellular proliferation induced by PDGF receptor activation.

Specific Inhibitors of Platelet-Derived Growth Factor or Epidermal Growth Factor Receptor Tyrosine Kinase Reduce Pulmonary Fibrosis in Rats

“…However, the doses of tyrphostins in this study were within the dose range used by other investigators investigating tyrosine kinase inhibitors under similar conditions. 25,26,33 Phosphorylation of the EGF-R may also be initiated by oxidant-generating environmental agents in the absence of EGF-R ligands, and in such cases it is important to consider the potential effects of AG1478 on this type of ligand-independent EGF-R activation. For example, asbestos fibers cause stimulation of a mitogen-activated protein (MAP) kinase signaling cascade after phosphorylation of the EGF-R, and asbestos-induced MAP kinase activation is blocked by AG1478.…”

“…20 Although several studies have documented the expression of PDGF-R, EGF-R, and their respective ligands during fibroproliferative diseases, the relative contribution of the EGF-R and the PDGF-R system to pulmonary fibrosis in relation to other growth factor receptors remains unknown. Inhibitors of PDGF receptor and EGF receptor tyrosine kinase activity have been reported for low molecular weight compounds of the staurosporine, 21 tyrphostin, 22,23 and 2-phenylaminopyrimidine 24,25 classes of compounds. Specific tyrphostin analogs have been reported to block a variety of pathogenic effects.…”

“…26 Furthermore, EGF-R-and PDGF-R-specific compounds of the 2-phenylaminopyrimidine class possess antitumor activity in vivo. 24,25 In this study we have investigated two tyrphostins, AG1296 and AG1478, that specifically block autophosphorylation of the PDGF-R and EGF-R, respectively. Using a rat model of metalinduced pulmonary fibrosis, we show that both AG1296 and AG1478 inhibit the proliferative response of epithelial and mesenchymal cells within fibrotic lesions, and this results in reduced lung collagen accumulation.…”

The oncogenic TEL/PDGFRβ fusion protein induces cell death through JNK/SAPK pathway

“…To determine whether the kinase activity of T/P is required for JNK/SAPK activation, we made the use of the protein kinase inhibitor (CGP53716) which is speci®c for PDGFR tyrosine kinase (Buchdunger et al, 1995) and completely inhibits the T/P-associated tyrosine kinase activity without modifying the overall pattern of tyrosine phosphorylation . Similarly, treatment of T/P-expressing Ba/F3 cells with CGP53716 completely inhibits JNK/SAPK activation ( Figure 2).…”

Platelet-derived Growth Factor Stimulation of Monocyte Chemoattractant Protein-1 Gene Expression Is Mediated by Transient Activation of the Phosphoinositide 3-Kinase Signal Transduction Pathway

“…We treated Balb/c 3T3 cells with PDGF in the presence or absence of STI571 (34). As shown, STI571 inhibited both PDGF receptor autophosphorylation (Fig.…”