Selective Itk inhibitors block T-cell activation and murine lung inflammation.
Biochemistry
; 43(34): 11056-62, 2004 Aug 31.
Article
em En
| MEDLINE
| ID: mdl-15323564
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.
Buscar no Google
Base de dados:
MEDLINE
Assunto principal:
Proteínas Tirosina Quinases
/
Ativação Linfocitária
/
Linfócitos T
/
Anti-Inflamatórios não Esteroides
/
Inibidores Enzimáticos
/
Pulmão
Idioma:
En
Ano de publicação:
2004
Tipo de documento:
Article