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

Tai An Lin, Kim W. McIntyre, Jagabandhu Das, Chunjian Liu, Kathleen D. O'Day, Becky Penhallow, Chen Yi Hung, Gena S. Whitney, David J. Shuster, Xiao Xia Yang, Robert Townsend, Jennifer Postelnek, Steven H. Spergel, James Lin, Robert V. Moquin, Joseph A. Furch, Amrita V. Kamath, Hongjian Zhang, Punit H. Marathe, Juan J. Perez-VillarArthur Doweyko, Loran Killar, John H. Dodd, Joel C. Barrish, John Wityak, Steven B. Kanner

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)11056-11062
Number of pages7
JournalBiochemistry
Volume43
Issue number34
DOIs
StatePublished - Aug 31 2004

All Science Journal Classification (ASJC) codes

  • Biochemistry

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