Jeffrey Herbert Hanke

Discovery of a Novel, Potent, and Src Family-selective Tyrosine Kinase Inhibitor STUDY OF Lck- 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 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.

Role of tyrosine kinases in lymphocyte activation: Targets for drug intervention

Recent developments in our understanding of lymphocyte receptor-associated signalling events have offered many new potential targets for modifying antigen and cytokine receptor signalling events in immune-related diseases such as allergy, autoimmunity and transplant rejection. As discussed below, these targets are largely tissue-restricted and are functionally confined to a limited set of receptors. Therefore, it is anticipated that selective inhibitors of these signalling events would offer safe and effective therapies for immunologically-based diseases. First, we review T and B cell antigen receptor signalling as targets for inhibiting lymphocyte responses. Second, targets in lymphocyte cytokine receptor signalling pathways are discussed. Finally, we review strategies for inhibition of receptor signalling.