Nonpeptidic, monocharged, cell permeable ligands for the p56lck SH2 domain

p561ck is a member of the src family of tyrosine kinases and plays a critic al role in the signal transduction events that lead to T cell activation. L igands for the p561ck SH2 domain have the potential to disrupt the interact ion of p561ck with its substrates and derail the signaling cascade that lea ds to the production of cytokines such as interleukin-2. Starting from the quintuply charged (at physiological pH) phosphorylated tetrapeptide, AcpYEE I, we recently disclosed (J. Med. Chem. 1999, 42, 722 and J. Med. Chem. 199 9, 42, 1757) the design of the modified dipeptide 3, which carries just two charges at physiological pH. Here we present the elaboration of 3 to the n onpeptidic, monocharged compound, 9S. This molecule displays good binding a ffinity for the p561ck SH2 domain (K-d 1 muM) and good cell permeation, and this combination of properties allowed us to demonstrate clear-cut inhibit ory effects on a very early event in T cell activation, namely calcium mobi lization.