title: Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation.
abstract: Here, we have studied the activity of a novel protein-tyrosine kinase inhibitor that is selective for the Src family of tyrosine kinases. We have focused our study on the effects of this compound on T cell receptor-induced T cell activation, a process dependent on the activity of the Src kinases Lck and FynT. This compound is a nanomolar inhibitor of Lck and FynT, inhibits anti-CD3-induced protein-tyrosine kinase activity in T cells, demonstrates selectivity for Lck and FynT over ZAP-70, and preferentially inhibits T cell receptor-dependent anti-CD3-induced T cell proliferation over non-T cell receptor-dependent phorbol 12-myristate 13-acetate/interleukin-2 (IL-2)-induced T cell proliferation. Interestingly, this compound selectively inhibits the induction of the IL-2 gene, but not the granulocyte-macrophage colony-stimulating factor or IL-2 receptor genes. This compound offers a useful new tool for examining the role of the Lck and FynT tyrosine kinases versus ZAP-70 in T cell activation as well as the role of other Src family kinases in receptor function.
authors.affiliation: Pfizer Central Research, Groton, Connecticut 06335, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Hanke
authors.forename: J P
authors.initials: JP
authors.lastname: Gardner
authors.forename: R L
authors.initials: RL
authors.lastname: Dow
authors.forename: P S
authors.initials: PS
authors.lastname: Changelian
authors.forename: W H
authors.initials: WH
authors.lastname: Brissette
authors.forename: E J
authors.initials: EJ
authors.lastname: Weringer
authors.forename: B A
authors.initials: BA
authors.lastname: Pollok
authors.forename: P A
authors.initials: PA
authors.lastname: Connelly
mesh_terms: D017252:CD3 Complex / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008213:Lymphocyte Activation; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D017252:CD3 Complex; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D019061:src-Family Kinases