TY - JOUR T1 - Inhibition of Human T Cell Activation by Novel Src Kinase Inhibitors Is Dependent upon the Complexity of the Signal Delivered to the Cell JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1325 LP - 1333 DO - 10.1124/jpet.102.038380 VL - 303 IS - 3 AU - Stephen Rapecki AU - Rodger Allen Y1 - 2002/12/01 UR - http://jpet.aspetjournals.org/content/303/3/1325.abstract N2 - The activity of a novel series of protein tyrosine kinase inhibitors that are selective for the Src family has been assessed. The activity of these compounds [named CT-SKI (Celltech Src kinase inhibitors)] was investigated by assessing their potential to modulate T cell receptor activation, an event thought to involve the Src kinases Lck and Fyn. This series of compounds contained low-nanomolar inhibitors of Src kinases with selectivity over Csk, epidermal growth factor receptor kinase, protein kinase C, and ζ-associated 70-kDa protein. These compounds were shown to attenuate anti-CD3-induced T cell proliferation and block interleukin (IL)-2, IL-4, and interferon-γ production, and CD25 expression in anti-CD3-activated T cells. In addition, inhibition of anti-CD3-induced, but not phorbol ester and calcium ionophore-induced IL-2 production, correlated with inhibition of in vitro Lck kinase activity. When more complex stimuli were used to activate T cells, as in the mixed lymphocyte reaction (MLR), these inhibitors proved to be less effective and inhibition of the MLR did not correlate with inhibition of isolated Lck enzyme. Interestingly, inhibition of anti-CD3-induced proliferation could be reversed by the addition of exogenous IL-2, indicating that signaling through the IL-2 receptor may not be critically dependent on any functional Src enzymes. ER -