Selective Itk inhibitors block T-cell activation and murine lung inflammation

TA Lin, KW McIntyre, J Das, C Liu, KD O'Day… - Biochemistry, 2004 - ACS Publications
TA Lin, KW McIntyre, J Das, C Liu, KD O'Day, B Penhallow, CY Hung, GS Whitney…
Biochemistry, 2004ACS Publications
Nonreceptor protein tyrosine kinases including Lck, ZAP-70, and Itk play essential roles in T-
cell receptor (TCR) signaling. Gene knockout studies have revealed that mice lacking these
individual kinases exhibit various degrees of immunodeficiency; however, highly selective
small molecule inhibitors of these kinases as potential immunosuppressive agents have not
been identified. Here we discovered two novel compounds, BMS-488516 and BMS-509744,
that potently and selectively inhibit Itk kinase activity. The compounds reduce TCR-induced …
Nonreceptor protein tyrosine kinases including Lck, ZAP-70, and Itk play essential roles in T-cell receptor (TCR) signaling. Gene knockout studies have revealed that mice lacking these individual kinases exhibit various degrees of immunodeficiency; however, highly selective small molecule inhibitors of these kinases as potential immunosuppressive agents have not been identified. Here we discovered two novel compounds, BMS-488516 and BMS-509744, that potently and selectively inhibit Itk kinase activity. The compounds reduce TCR-induced functions including PLCγ1 tyrosine phosphorylation, calcium mobilization, IL-2 secretion, and T-cell proliferation in vitro in both human and mouse cells. The inhibitors suppress the production of IL-2 induced by anti-TCR antibody administered to mice. BMS-509744 also significantly diminishes lung inflammation in a mouse model of ovalbumin-induced allergy/asthma. Our findings represent the first description of selective inhibitors to probe human Itk function and its associated pathway, and support the hypothesis that Itk is a therapeutic target for immunosuppressive and inflammatory diseases.
ACS Publications