TARKINAID objectives

Objective 1: Generation of novel anti-inflammatory molecules that act on Src-family kinases


The TARKINAID project aims to develop novel anti-inflammatory molecules whose primary mode of action is their inhibitory effect on members of the Src tyrosine kinase family.
Using genetic approaches, members of the TARKINAID consortium have previously shown that Src-family kinases are indispensable for a number of inflammation-related in vitro functions of leukocytes, as well as for the development of various in vivo animal models of autoimmune inflammatory diseases. The TARKINAID consortium has also identified a number of novel small-molecule kinase inhibitors that inhibit members of the Src kinase family and they also block in vitro neutrophil functions. Those molecules serve as lead molecules for further drug optimization.

The effect of various novel Src-family tyrosine kinase inhibitors are tested on various in vitro inflammation-related assays such as neutrophil, macrophage and osteoclast activation, cytokine production, reactive oxygen species production, degranulation, migration and cell biological functions. The effect of the inhibitors are also tested on various short-term and chronic autoimmune inflammatory diseases in mice, such as various autoimmune arthritis models, chronic lung inflammation models, skin blistering models and in vivo models of certain components of the pathogenesis of the inflammatory cascade such as cellular migration or the Arthus reaction. The compounds go through multi-step iterations to optimize their structure for an in vivo anti-inflammatory effect.

 

Objective 2: Analysis of the anti-inflammatory effect of Src-family kinase inhibitors currently used in oncology patients


The aim of these studies is the analysis of the anti-inflammatory effect of two multi-kinase inhibitors with strong effect on Src-family kinases which are currently used in the therapy of malignant diseases, primarily Philadelphia chromosome-positive chronic myeloid leukemia.

The two multi-kinase inhibitors are tyrosine kinase inhibitors already in clinical use for oncology patients; therefore they have already passed rigorous testing of safety, bioavailability and pharmacokinetic properties. Since a) these molecules exert strong inhibitory effect on Src-family kinases, b) our own prior genetic studies provided strong evidence for the role of Src-family kinases in autoimmune and inflammatory diseases and c) in vitro studies have indicated strong inhibition of neutrophil functions by therapeutic concentrations of the two multi-kinase inhibitors, it is reasonable to assume that the two compounds have an inhibitory effect on certain other in vitro inflammation-related functions, as well as the development of autoimmune and inflammatory diseases in animal models.

The effect of multi-kinase inhibitors are being tested on various in vitro inflammation-related assays such as neutrophil, macrophage and osteoclast activation, cytokine production, reactive oxygen species production, degranulation, migration and cell biological functions. The effect of multi-kinase inhibitors are also tested on various short-term and chronic autoimmune inflammatory diseases in mice, such as various autoimmune arthritis models, chronic lung inflammation models, skin blistering models and in vivo models of certain components of the pathogenesis of the inflammatory cascade such as cellular migration or the Arthus reaction. The effect of multi-kinase inhibitors will be compared with those of a Syk tyrosine kinase inhibitor in clinical testing/use for the therapy of rheumatoid arthritis.

 

Objective 3: Genetic analysis of the role of Src-family kinases in inflammation


The TARKINAID project aims to obtain further detailed information on the role of Src-family kinases in in vivo inflammatory processes. This would provide additional reference knowledge for the development of Src-family inhibitor anti-inflammatory compounds.

Prior studies from members of the TARKINAID consortium have shown that Src-family kinases play important roles in various inflammation-related in vitro functions of leukocytes, as well as in the development of various in vivo animal models of autoimmune inflammatory diseases. Those studies are being further extended in this objective.

The effect of mice with single or combined deficiency of the myeloid specific Src-family kinases Hck, Fgr and Lyn are tested in various in vitro inflammation-related assays such as neutrophil, macrophage and mast cell activation, cytokine production, reactive oxygen species production, degranulation and cell biological functions. The effect of the single or combined deficiency of myeloid Src-family kinases are also tested on various short-term and chronic autoimmune inflammatory diseases in mice, such as various autoimmune arthritis models, chronic lung inflammation models, skin blistering models and in vivo models of certain components of the pathogenesis of the inflammatory cascade such as cellular migration or the Arthus reaction.

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