Tyrosine Kinase Inhibitors Found to Prevent Certain Inflammatory Conditions

Results published recently suggest that two chronic inflammatory and possibly autoimmune disorders, Crohn's disease and sarcoidosis, may be treatable with anticancer drugs that are already on the market.

Investigators at Case Western Reserve University (Cleveland, OH, USA) examined the relationship between the Crohn's disease and sarcoidosis susceptibility protein NOD2 (nucleotide oligomerization domain protein 2) and its binding partner the protein kinase RIP2 (receptor-interacting protein 2). The interaction between these two proteins regulates NF-kappa B (nuclear factor kappa B)-mediated cytokine responses.

Although originally classified as a serine–threonine kinase based on homology scans, the current study found that RIP2 also has tyrosine kinase activity, and that RIP2 undergoes autophosphorylation at tyrosine residue 474. This phosphorylation event is necessary for effective NOD2 signaling and does not occur in the presence of the most common Crohn's disease-associated NOD2 allele.

Based on the finding of tyrosine kinase activity, the investigators conducted a small-molecule inhibitor screen designed to identify pharmacologic agents that inhibit RIP2's tyrosine kinase activity. They reported in the December 1, 2010, issue of the journal Genes & Development that the EGFR (epidermal growth factor receptor) tyrosine kinase inhibitors and anticancer chemotherapeutic agents gefitinib (Iressa) and erlotinib (Tarceva) inhibited both RIP2 tyrosine phosphorylation and MDP (muramyl dipeptide)-induced cytokine release in a variety of NOD2 hyperactivation states. This effect was specific for RIP2 and did not depend on EGFR.

"While these findings offer a potentially beneficial avenue for the treatment of two serious inflammatory diseases, further testing is necessary to substantiate our initial promising findings. Further testing is also necessary to validate the safety and potential efficacy of these agents in both Crohn's disease and sarcoidosis,” said senior author Dr. Derek Abbott, assistant professor of pathology at Case Western Reserve University. "However, these studies also show that very basic biochemical research can lead to findings that could have clinical impact.”

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