Discovery of a Novel, Potent, and Src Family-selective Tyrosine Kinase Inhibitor

doi:10.1074/jbc.271.2.695

Discovery of a Novel, Potent, and Src Family-selective Tyrosine Kinase Inhibitor

STUDY OF Lck- AND FynT-DEPENDENT T CELL ACTIVATION (*)

From the From Pfizer Central Research, Groton, Connecticut 06335

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Pfizer Central Research, Eastern Point Rd., Groton, CT 06340.
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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.

Footnotes

↵* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

TcR

T cell receptor

IL-2

interleukin-2

IL-2R

IL-2 receptor

EGF-R

epidermal growth factor receptor

GM-CSF

granulocyte-macrophage colony-stimulating factor

PBL

peripheral blood lymphocyte(s)

PBS

phosphate-buffered saline

PMA

phorbol 12-myristate 13-acetate

PHA

phytohemagglutinin

PAGE

polyacrylamide gel electrophoresis.
- Received September 20, 1995.