Targeted therapeutic immune response modulators

The protein p56 lymphoid T-cell tyrosine kinase (Lck) is predominantly expressed in T lymphocytes where it plays a critical role in T-cell-mediated immune response. Lck participates in phosphotyrosine-dependent protein-protein interactions through its modular binding unit, the Src homology-2 (SH2) domain. SH2 domains are noncatalytic modules of about 100 amino acid residues that play important roles in intracellular signal transduction and represent potential targets for pharmacological intervention. Failure of the p5 6 Lck S H 2 domain to bind to immunoreceptor tyrosine-based activation motifs (ITAMs) of CD3 hampers the T-cell receptor (TCR) proximal activation process and suppresses the downstream T-cell activation signaling cascades [143]. Small compounds that would be able to block Lck SH2 domain-dependent protein-protein interactions could find therapeutic utility as immunosuppressants and in the treatment of T-cell leukemias, lymphomas, and autoimmune diseases such as rheumatoid arthritis. 

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