Chronic inflammatory diseases such as rheumatoid arthritis, psoriasis, psoriatic arthritis and intestinal inflammation affect a total of 2-3% of the world's population. Extensive studies by our research team have highlighted the key role that Tumor Necrosis Factor (TNF) and mesenchymal cells / fibroblasts play  in the pathogenic mechanisms underlying these diseases. Since the early 90s, therapeutic approaches mainly targeted the pathogenic action of TNF, leading to the rapid development of anti-TNF biologics. However these therapies have many side effects and disadvantages, such as immunosuppression and progressively reduced response to treatment. Aiming at developing new approaches for the treatment of inflammatory diseases, Fleming's research team has developed innovative methods to successfully reposition commercially available drugs. Preliminary studies revealed a pharmaceutical compound (GKL09) approved for a different indication as an inhibitor of the TNF signaling pathway in activated mesenchymal cells (synovial fibroblasts). The effect of GKL09 was also confirmed in vivo, significantly suppressing the arthritic phenotype in the experimental animal model of arthritis overexpressing TNF.

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This project aims at synthesizing and refining novel small molecules against chronic inflammatory diseases, using GKL09 and its optimized derivatives, as lead compounds. The most promising candidates will be further studied for their mechanism of action and therapeutic potential in animal models of chronic inflammatory diseases.

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The originality of the proposed work focuses on four parameters: (i) the targeting of a cell type (mesenchymal cells) that to date has not been exploited therapeutically, even though it has been shown to play a key role in the pathogenesis of chronic inflammatory diseases,  (ii) the development of new drugs using lead compounds with already proven preclinical in vivo activity; (iii) the discovery of novel small molecules / TNF inhibitors in high demand from the market as successors of current  biological treatments, and (iv) the maturity of the exploitation plan, as interest for collaboration already exists by potential investors.