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

  • Biochemistry. 2004 Aug 31;43(34):11056-62. doi: 10.1021/bi049428r.
Tai-An Lin  1 ,  Kim W McIntyre ,  Jagabandhu Das ,  Chunjian Liu ,  Kathleen D O'Day ,  Becky Penhallow ,  Chen-Yi Hung ,  Gena S Whitney ,  David J Shuster ,  XiaoXia 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-Villar ,  Arthur Doweyko ,  Loran Killar ,  John H Dodd ,  Joel C Barrish ,  John Wityak ,  Steven B Kanner
Affiliations
  • 1. Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA. [email protected]
PMID: 15323564 DOI: 10.1021/bi049428r
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 PLCgamma1 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.

Products