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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 ␤1 and type I collagen, and this result correlated with the inhibition ability of the compound against enhanced expression of ␣-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-␣ 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.

Discoidin domain receptors (DDRs), consisting of two closely related receptor types I and II, were originally found as an orphan receptor tyrosine kinase overexpressed in cancer cells.1,2) Later various types of collagens were identified as their activating ligand, indicating that they function to transmit signals from the extracellular matrix to inside the cells. 3,4) Five isoforms of DDR1 have been reported, which have differences in the cytoplasmic domain generated by alternative splicing, whereas DDR2 showed a single form. 5)Collagen type I, II, III, IV and VIII activate DDR1, whereas DDR2 is activated by type I, II, III and X. 3,4,6) The N-terminal extracellular domain of DDRs contains a stretch of about 150 amino acids, termed the discoidin domain, 1) which is critical for their binding to collagens. [7][8][9] The cytosolic domain of DDRs contains a tyrosine kinase motif whereby it is auto-phosphorylated, by activation with collagen, to transduce signals. 3,4) Activated signaling of DDR2 promotes fibroblast cell growth and migration through the induction of matrix metalloprotease (MMP) proteins. 10) As DDR2 has been linked to regulation of cell growth, its enhanced expression was observed in various human pathogenesis. Increased mRNA of DDR2 was found in classical Hodgkin's Lymphoma cells, 11) nasopharyngeal carcinoma 12) and correlated with the invasive property of mammary carcinoma cell lines.13) Elevated tyrosine phosphorylation of DDR2 was frequently detected in tumor samples of non small cell lung carcinoma.14)The increased synthesis and continuous activation of DDR2 was responsible for the over-proliferation of stellate cells and deregulated accumulation of fiber collagens in liver cirrhosis.15) High expression levels of DDR2 were detected in chondrocytes of an osteoathritic mouse model, which resulted in the upregulation of matrix metalloprotease-13 (MMP-13). MMP-13 is one of the main proteases that degrades collagen within the cartilage of osteoathritic patients.16) Synovial fibroblast isolated from the joint region of rheumatoid arthritis patients was reported to express a high level of DDR2, which then induces the synthesis of a large amount of matrix metalloprotease-1 that causes a serious damage on the cartilage.17) These studies imply that inhibition of DDR2 signaling could be a therapeutic approach and the development of inhibitors to prevent the activation of DDR2 by its ligand could be a useful strategy for the therapeutic agents.Actinomycin D is an antibiotic compound that has been clinically used for a long time as an anticancer drug to treat wilms' tumor, rhabdomyosarcoma, Ewing's sarcoma, trophoblastic neoplasia and testicular carcinoma. 18,19) The anticancer mechanism of actinomycin D has been thought to be mediated by its activity to intercalate into DNA and to inhibit RNA synthesis by binding to guanine residues and inhibiting DNA-dependent RNA polymerase. 20)In this paper, we found a new biological function of actinomycin D to interfere the activation of DDR2 by its ligand collagen...

Malignant gliomas have retained their dismal prognosis despite aggressive multimodal conventional therapeutic approaches, illustrating the need for novel therapeutic strategies. Recent advances in the cellular and molecular biology of gliomas have enhanced our understanding of the role of receptor tyrosine kinases (RTK) and RTK-mediated signal transduction pathways in tumor initiation, maintenance, angiogenesis, and vascular proliferation. Special attention has been focused on targets such as epidermal growth factor receptors (EGFR), platelet-derived growth factor receptors (PDGFR), vascular endothelial growth factor receptors (VEGFR), and on pathways such as the Ras/Raf/mitogen-activated protein (MAP)-kinase and phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways. Novel targeted drugs known as small molecule inhibitors have been shown to modify the activity of these receptors and signaling pathways. Thus far, however, small molecule RTK inhibitor development has concentrated on a few RTK only, and drug activity has been comprehensively evaluated only in a limited number of different malignancies. One of the limiting factors for novel drug design and development is the incomplete knowledge of RTK functions in malignant glioma. This review summarizes current basic and clinical knowledge on the role of RTK in malignant glioma and on their importance as targets for new forms of therapy.

Abbreviations: ATP, adenosine triphosphate; CDK, cell cycle dependent kinase; FBS: fetal bovine serum; GST: glutathione-Stransferase; MOI: multitude of infection; RB, retinoblastoma protein; RBC: human RB C-terminal protein from amino acid 780 to 928; SDS: sodium dodesyl sulfate