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.