Inhibitors of p56lck:: assessing their potential as tools for manipulating T-lymphocyte activation

The Src family tyrosine kinase p56(lck) is predominantly expressed in T-lymphocytes and natural killer cells and there is an absolute requirement for p56lck in T-cell development and activation. Consequently, there has been much effort in developing small molecule antagonists for p56(lck) with a view for therapeutic use in a number of T-lymphocyte-dependent diseases. A large majority of protein kinase inhibitors are directed toward the ATP binding site and gain their specificity by exploiting adjacent topographical variations. To date, the most potent and widely studied class of Lck inhibitors are the pyrazolopyrimidines, which have proven to be valuable research tools. The development of pyrido[2,3-d]pyrimidine structures offer excellent potency and selectivity from a different structural platform and together these appear to offer the most promising scaffolds for the development of future therapeutics. SH2 domain inhibition offers the potential reward of escaping the constraints of the ATP binding site but developing potent and specific inhibitors of protein-protein interactions presents a significant challenge. The results briefly discussed in this review reveal the extent of progress toward this goal.