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Lin, Tai-An; McIntyre, Kim W; Das, Jagabandhu; Liu, Chunjian; O'Day, Kathleen D; Penhallow, Becky; Hung, Chen-Yi; Whitney, Gena S; Shuster, David J; Yang, XiaoXia; Townsend, Robert; Postelnek, Jennifer; Spergel, Steven H; Lin, James; Moquin, Robert V; Furch, Joseph A; Kamath, Amrita V; Zhang, Hongjian; Marathe, Punit H; Perez-Villar, Juan J; Doweyko, Arthur; Killar, Loran; Dodd, John H; Barrish, Joel C; Wityak, John; Kanner, Steven B
Biochemistry (Easton), 08/2004, Volume: 43, Issue: 34Journal Article
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.
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