The project aims to develop novel inhibitors of chronic autoimmune and inflammatory diseases by targeting members of the Src tyrosine kinase family. Src-family kinases have recently emerged as major therapeutic targets in malignant diseases but their suitability as potential targets of inflammatory diseases has not yet recieved widespread acceptance. On the other hand, members of the applicant consortium have recently obtained genetic evidence showing that myeloid Src-family kinases (Hck, Fgr and Lyn) are indispensable for murine models of autoimmune inflammatory diseases such as rheumatoid arthritis or blistering skin diseases. They also developed a number of novel Src-family kinase inhibitors that also block inflammation-related in vitro leukocyte functions. The applicants will test and further develop novel Src-family kinase inhibitors as anti-inflammatory compounds, using several in vitro and in vivo inflammation assays to optimize the structure of the selected molecules. They will also test whether Src-family inhibitors already in clinical use in oncology patients also inhibit inflammatory processes. Finally, they will use Src-family kinase-deficient mice in several inflammation models to test the role of those kinases in more detail and to provide further reference information for the consortium's preclinical drug development activity. The selected inhibitors and mutant mice will be pre-screened using various inflammation-related in vitro leukocyte functions and short-term in vivo inflammation models, and then analyzed in detail using a number of in vivo mouse models of chronic autoimmune and inflammatory diseases. The project is expected to result in development of novel preclinical drug candidates against chronic autoimmune and inflammatory disease with novel mechanism of action, as well as novel knowledge on the role of Src-family kinases in inflammatory diseases. The project will be performed in close cooperation between European and Brazilian scientists.