title: LCB 03-0110, a novel pan-discoidin domain receptor/c-Src family tyrosine kinase inhibitor, suppresses scar formation by inhibiting fibroblast and macrophage activation.
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.
authors: Korea Institute of Science and Technology, 39-1, Hawolgok-Dong, Sungbuk-Ku, Seoul 136-791, Korea.
authors: Xiaoyan
authors: X
authors: Sun
authors: Trong Nhat
authors: TN
authors: Phan
authors: Seung Hee
authors: SH
authors: Jung
authors: Sun Young
authors: SY
authors: Kim
authors: Jong Un
authors: JU
authors: Cho
authors: Hyangsook
authors: H
authors: Lee
authors: Sung Ho
authors: SH
authors: Woo
authors: Tae Kyo
authors: TK
authors: Park
authors: Beom-Seok
authors: BS
authors: Yang
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D002921:Cicatrix / Q000517:prevention & control*; D000070818:Discoidin Domain Receptors; D005260:Female; D005347:Fibroblasts / Q000187:drug effects*; D006801:Humans; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D011817:Rabbits; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011975:Receptors, Mitogen / Q000037:antagonists & inhibitors*; D013876:Thiophenes / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: C571281:3-(2-(3-(morpholinomethyl)phenyl)thieno(3,2-b)pyridin-7-ylamino)phenol; D000631:Aminopyridines; D011975:Receptors, Mitogen; D013876:Thiophenes; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; D019061:src-Family Kinases