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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleCARDIOVASCULAR

Efficacy of the Novel Selective Platelet-Derived Growth Factor Receptor Antagonist CT52923 on Cellular Proliferation, Migration, and Suppression of Neointima following Vascular Injury

Jin-Chen Yu, Nathalie A. Lokker, Stanley Hollenbach, Mutiah Apatira, Jason Li, Andreas Betz, David Sedlock, Shoji Oda, Yuji Nomoto, Kenji Matsuno, Shin-ichi Ide, Eiji Tsukuda and Neill A. Giese
Journal of Pharmacology and Experimental Therapeutics September 2001, 298 (3) 1172-1178;
Jin-Chen Yu
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Nathalie A. Lokker
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Stanley Hollenbach
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Mutiah Apatira
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Jason Li
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Andreas Betz
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David Sedlock
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Shoji Oda
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Yuji Nomoto
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Kenji Matsuno
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Shin-ichi Ide
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Eiji Tsukuda
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Neill A. Giese
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Abstract

Exaggerated or inappropriate signaling by the platelet-derived growth factor receptor (PDGFR) tyrosine kinase has been implicated in a wide variety of diseases. Thus, a series of piperazinyl quinazoline compounds were identified as potent antagonists of the PDGFR by screening chemical libraries. An optimized analog, CT52923, was shown to be an ATP-competitive inhibitor that exhibited remarkable specificity when tested against other kinases, including all members of the closely related PDGFR family. The PDGFRs and stem cell factor receptor were inhibited with an IC50 of 100 to 200 nM, while 45- to >200-fold higher concentrations of CT52923 were required to inhibit fms-like tyrosine kinase-3 and colony-stimulating factor-1 receptor, respectively. Other receptor tyrosine kinases, cytoplasmic tyrosine kinases, serine/threonine kinases, or members of the mitogen-activated protein kinase pathway were not significantly inhibited at 100- to 1000-fold higher concentrations. In addition, this compound also demonstrated specificity for inhibition of cellular responses. Platelet-derived growth factor-induced smooth muscle cell migration or fibroblast proliferation was found to be blocked by CT52923 with an IC50 of 64 and 280 nM, respectively, whereas 50- to 100-fold higher concentrations were required to inhibit these responses when induced with fibroblast growth factor. To investigate the effect of CT52923 on PDGFR signaling, in vivo studies demonstrated that CT52923 could significantly inhibit neointima formation following carotid artery injury by oral administration in the rat. Therefore, PDGFR antagonism by CT52923 could be a viable strategy for the prevention of clinical restenosis or the treatment of other human diseases involving PDGFR signaling.

Footnotes

  • Abbreviations:
    PDGF
    platelet-derived growth factor
    PDGFR
    platelet-derived growth factor receptor
    CHO
    Chinese hamster ovary
    CSF-1R
    colony-stimulating factor-1 receptor
    c-Kit
    stem cell factor receptor
    Flt3
    fms-like tyrosine kinase-3
    VEGFR-2
    vascular endothelial growth factor receptor 2
    RT-PCR
    reverse transcription-polymerase chain reaction
    FGFR-1
    fibroblast growth factor receptor-1
    mAb
    monoclonal antibody
    EGFR
    epidermal growth factor receptor
    EGF
    epidermal growth factor
    FGF
    fibroblast growth factor
    PK
    protein kinase
    bFGF
    basic fibroblast growth factor
    MAPK
    mitogen-activated protein kinase
    • Received March 2, 2001.
    • Accepted June 1, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 3
1 Sep 2001
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Research ArticleCARDIOVASCULAR

Efficacy of the Novel Selective Platelet-Derived Growth Factor Receptor Antagonist CT52923 on Cellular Proliferation, Migration, and Suppression of Neointima following Vascular Injury

Jin-Chen Yu, Nathalie A. Lokker, Stanley Hollenbach, Mutiah Apatira, Jason Li, Andreas Betz, David Sedlock, Shoji Oda, Yuji Nomoto, Kenji Matsuno, Shin-ichi Ide, Eiji Tsukuda and Neill A. Giese
Journal of Pharmacology and Experimental Therapeutics September 1, 2001, 298 (3) 1172-1178;

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Research ArticleCARDIOVASCULAR

Efficacy of the Novel Selective Platelet-Derived Growth Factor Receptor Antagonist CT52923 on Cellular Proliferation, Migration, and Suppression of Neointima following Vascular Injury

Jin-Chen Yu, Nathalie A. Lokker, Stanley Hollenbach, Mutiah Apatira, Jason Li, Andreas Betz, David Sedlock, Shoji Oda, Yuji Nomoto, Kenji Matsuno, Shin-ichi Ide, Eiji Tsukuda and Neill A. Giese
Journal of Pharmacology and Experimental Therapeutics September 1, 2001, 298 (3) 1172-1178;
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