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Research ArticleDrug Discovery and Translational Medicine

LCB 03-0110, a Novel Pan-Discoidin Domain Receptor/c-Src Family Tyrosine Kinase Inhibitor, Suppresses Scar Formation by Inhibiting Fibroblast and Macrophage Activation

Xiaoyan Sun, Trong Nhat Phan, Seung Hee Jung, Sun Young Kim, Jong Un Cho, Hyangsook Lee, Sung Ho Woo, Tae Kyo Park and Beom-Seok Yang
Journal of Pharmacology and Experimental Therapeutics March 2012, 340 (3) 510-519; DOI: https://doi.org/10.1124/jpet.111.187328
Xiaoyan Sun
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Trong Nhat Phan
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Seung Hee Jung
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Sun Young Kim
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Jong Un Cho
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Hyangsook Lee
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Sung Ho Woo
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Tae Kyo Park
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Beom-Seok Yang
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Abstract

Wound healing generally induces an inflammatory response associated with tissue fibrosis in which activated macrophage and myofibroblast cells are primarily involved. Although this is known to be the underlying mechanism for scarring and various fibrotic pathologies, no effective intervention is currently available. We identified (3-(2-(3-(morpholinomethyl)phenyl)thieno[3,2-b]pyridin-7-ylamino)phenol (LCB 03-0110), a thienopyridine derivative, as a potent inhibitor of discoidin domain receptor family tyrosine kinases and discovered that this compound strongly inhibits several tyrosine kinases, including the c-Src family, spleen tyrosine kinase, Bruton's tyrosine kinase, and vascular endothelial growth factor receptor 2, which are important for immune cell signaling and inflammatory reactions. LCB 03-0110 suppressed the proliferation and migration of primary dermal fibroblasts induced by transforming growth factor β1 and type I collagen, and this result correlated with the inhibition ability of the compound against enhanced expression of α-smooth muscle actin and activation of Akt1 and focal adhesion kinase. In J774A.1 macrophage cells activated by lipopolysaccharide LCB 03-0110 inhibited cell migration and nitric oxide, inducible nitric-oxide synthase, cyclooxygenase 2, and tumor necrosis factor-α synthesis. LCB 03-0110 applied topically to full excisional wounds on rabbit ears suppressed the accumulation of myofibroblast and macrophage cells in the healing wound and reduced hypertrophic scar formation after wound closing, without delaying the wound closing process. Taken together, the pharmacological activities of LCB 03-0110 suggest that it could be an effective agent for suppressing fibroinflammation by simultaneously targeting activated fibroblasts and macrophages.

Footnotes

  • This study was supported by the Korea Institute of Science and Technology [Grant 2V01550] and LegoChem Biosciences Inc. [Grant 2I20750].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.187328.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    NO
    nitric oxide
    iNOS
    inducible nitric-oxide synthase
    DDR
    discoidin domain receptor
    FAK
    focal adhesion kinase
    LPS
    lipopolysaccharide
    TNF
    tumor necrosis factor
    COX
    cyclooxygenase
    PDGF
    platelet-derived growth factor
    TGF
    transforming growth factor
    VEGF
    vascular endothelial growth factor
    Btk
    Bruton's tyrosine kinase
    Syk
    spleen tyrosine kinase
    FLT
    fms-like tyrosine kinase
    Hck
    hematopoietic cell kinase
    Lck
    lymphocyte-specific protein tyrosine kinase
    ECM
    extracellular matrix
    DMEM
    Dulbecco's modified Eagle's media
    HEK
    human embryonic kidney
    FBS
    fetal bovine serum
    TBS
    Tris-buffered saline
    HPF
    high-power field
    RTK
    receptor tyrosine kinase
    JNK
    c-Jun NH2-terminal kinase
    MAPK
    mitogen-activated protein kinase
    IκB
    inhibitor of nuclear factor-κB
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    Eph
    ephrin
    LCB 03-0110
    (3-(2-(3-(morpholinomethyl)phenyl)thieno[3,2-b]pyridin-7-ylamino)phenol.

  • Received August 31, 2011.
  • Accepted November 28, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 3
1 Mar 2012
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Research ArticleDrug Discovery and Translational Medicine

A DDR/Src Family Kinase Inhibitor Suppressing Scar Formation

Xiaoyan Sun, Trong Nhat Phan, Seung Hee Jung, Sun Young Kim, Jong Un Cho, Hyangsook Lee, Sung Ho Woo, Tae Kyo Park and Beom-Seok Yang
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 510-519; DOI: https://doi.org/10.1124/jpet.111.187328

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Research ArticleDrug Discovery and Translational Medicine

A DDR/Src Family Kinase Inhibitor Suppressing Scar Formation

Xiaoyan Sun, Trong Nhat Phan, Seung Hee Jung, Sun Young Kim, Jong Un Cho, Hyangsook Lee, Sung Ho Woo, Tae Kyo Park and Beom-Seok Yang
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 510-519; DOI: https://doi.org/10.1124/jpet.111.187328
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