Anticancer drugs for chronic inflammation

Src-family kinases (SFKs) recently emerged as major therapeutic targets in malignant diseases, but their suitability as potential targets of AI and IDs have not been investigated in depth. SFKs are non-receptor tyrosine kinases implicated in diverse biological functions such as cellular proliferation and invasion.

Recent studies in genetically modified mice found that SFKs in leukocytes play an indispensable role in animal models of various chronic AI and IDs. Based on these results, the EU-funded TARKINAID (Targeting Src-family tyrosine kinases in chronic autoimmune and inflammatory diseases) consortium aims to develop novel inhibitors of chronic AI and IDs by targeting SFK members.

During the first 18 months of the project, scientists tested in vitro and in vivo the toxicity of 13 lead compounds as well as their effect on inflammatory reactions. They also generated a novel 1 000-member sub-library consisting of compounds chemically related to the original 13 compounds and tested their efficacy on SFKs in vitro.

Dasatinib is a known inhibitor of SFKs. Testing revealed novel in vitro effects, including inhibition of the activation and migration of neutrophils and macrophages, as well as a dramatic inhibitory effect on osteoclast development. In vivo inhibitory effects were demonstrated in the various transgenic models of arthritis development, resulting in improved lung function in lung damage models and protection in infection models.

During the second project phase, TARKINAID identified five novel inhibitors that were more effective than dasatinib in in vitro and in vivo tests. Compounds such as C2 were found to inhibit contact hypersensitivity, whereas bosutinib did not prove to be as effective as C2 and dasatinib.

Using transgenic mice, TARKINAID uncovered novel functions of the myeloid SFKs Hck, Fgr and Lyn in the generation of an inflammatory environment.

Results of the investigation have so far been presented at several international meetings and in over 20 scientific publications.

This project represents the first comprehensive approach in Europe to validate the use of SFK-inhibiting drugs as anti-inflammatory agents during chronic inflammation in vivo. The project has the potential to develop entirely novel small-molecule inhibitors as oral anti-inflammatory therapeutics.