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Selective inhibition of platelet-derived growth factor (PDGF) receptor autophosphorylation and PDGF-mediated cellular events by a quinoline derivative. 1997

M Yagi, and S Kato, and Y Kobayashi, and K Kubo, and S Oyama, and T Shimizu, and T Nishitoba, and T Isoe, and K Nakamura, and H Ohashi, and N Kobayashi, and N Iinuma, and T Osawa, and R Onose, and H Osada
Pharmaceutical Research Laboratory, Kirin Brewery Company, Ltd., Takasaki-shi, Japan. m-yagi@kirin.co.jp

This report describes the biological effects of our original compound, Ki6783 ((3,4-dimethoxy)-4-phenoxy-6,7-dimethoxyquinoline), a potent and selective inhibitor of platelet-derived growth factor (PDGF) receptor autophosphorylation. This compound strongly inhibited autophosphorylation of the PDGF beta-receptor in cultured rat glomerular mesangial cells (MC) bearing this receptor (IC50 0.1 microM), although it did not inhibit autophosphorylation of other growth factor receptors even at 100 microM. In a cell-free kinase experiment, it showed selective inhibition of PDGF beta-receptor tyrosine kinase. A kinetic study of the compound to this tyrosine kinase revealed a competitive mode of action to ATP. [3H]Thymidine incorporation and cell proliferation of MC were inhibited by Ki6783 in a dose-dependent manner after Ki6783 and PDGF-BB were added to the culture medium. Furthermore, this compound normalized the fibrotic cell shape of v-sis-transformed NIH3T3 cells, which grow in an autocrine manner via the PDGF receptor. These effects could be explained by the inhibition of intracellular signal transduction triggered by PDGF receptor autophosphorylation, in which activation of mitogen-activated protein kinase occurs. These results suggest that Ki6783 is one of the more potent and selective inhibitors of PDGF receptor autophosphorylation and that it may be useful in ameliorating cell abnormalities due to excess action of PDGF and its receptor systems in several diseases.

UI MeSH Term Description Entries
D007700 Kinetics The rate dynamics in chemical or physical systems.
D008297 Male Males
D010766 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Phosphorylations
D010982 Platelet-Derived Growth Factor Mitogenic peptide growth hormone carried in the alpha-granules of platelets. It is released when platelets adhere to traumatized tissues. Connective tissue cells near the traumatized region respond by initiating the process of replication. Platelet Derived Growth Factor,Factor, Platelet-Derived Growth,Growth Factor, Platelet-Derived
D011804 Quinolines
D011921 Rats, Inbred WKY A strain of Rattus norvegicus used as a normotensive control for the spontaneous hypertensive rats (SHR). Rats, Wistar Kyoto,Wistar Kyoto Rat,Rats, WKY,Inbred WKY Rat,Inbred WKY Rats,Kyoto Rat, Wistar,Rat, Inbred WKY,Rat, WKY,Rat, Wistar Kyoto,WKY Rat,WKY Rat, Inbred,WKY Rats,WKY Rats, Inbred,Wistar Kyoto Rats
D002455 Cell Division The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION. M Phase,Cell Division Phase,Cell Divisions,Division Phase, Cell,Division, Cell,Divisions, Cell,M Phases,Phase, Cell Division,Phase, M,Phases, M
D002461 Cell Line, Transformed Eukaryotic cell line obtained in a quiescent or stationary phase which undergoes conversion to a state of unregulated growth in culture, resembling an in vitro tumor. It occurs spontaneously or through interaction with viruses, oncogenes, radiation, or drugs/chemicals. Transformed Cell Line,Cell Lines, Transformed,Transformed Cell Lines
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D004247 DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA, Double-Stranded,Deoxyribonucleic Acid,ds-DNA,DNA, Double Stranded,Double-Stranded DNA,ds DNA

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