DISCOVERY OF A NOVEL, POTENT, AND SRC FAMILY-SELECTIVE TYROSINE KINASE INHIBITOR - STUDY OF LCK-DEPENDENT AND FYNT-DEPENDENT T-CELL ACTIVATION

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 rece ptor-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-CDS-induced protein-tyrosine kinase act ivity in T cells, demonstrates selectivity for Lck and FynT over ZAP-7 0, and preferentially inhibits T cell receptor-dependent anti-CD3-indu ced T cell proliferation over non-T cell receptor-dependent phorbol 12 -myristate 13-acetate/interleukin-2 (IL-S) induced T cell proliferatio n, Interestingly, this compound selectively inhibits the induction of the IL-2 gene, but not the granulocyte macrophage colony-stimulating f actor or IL-2 receptor genes, This compound offers a useful new tool f or 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 kinas es in receptor function.