Phosphotyrosyl-Based Motifs in the Structure-Based Design of Protein­ Tyrosine Kinase-Dependent Signal Transduction Inhibitors

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Abstract
Transmission of extracellular signals from the cell membrane to the nucJeus depends on modification of phosphorylation states of intracellular proteins. Tyrosine, serine and threonine residues are the principal amino acid targets of these phosphorylation events, with tyrosyl residues being particularly important for pathways mediated by growth factors and cytokines. Aberrations in phosphotyrosyl (pTyr)­ dependent signalling can contribute to a variety of diseases, including canc.ers, and for this reason selective modulation of pTyr-dependent signalling may afford new therapeutic approaches. The design of such therapeutics is facilitated by the functional compartmen­ talization of pTyr dependent signalling into three broad categories: ( l) the generation of pTyr residues by protein-tyrosine kinases (PTK); (2) pTyr-dependent protein-protein associations mediated by binding modules such as Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains and (3) the dephosphorylation of pTyr residues by protein-tyrosine phosphatases (PTPs). The pTyr residue itself, which is a unifying component of this signalling triad, potentially affords a starting point for the design of antagonists. In the PTK, SH2/PTB and PTP domain signalling environments, the pTyr residue plays unique roles by participating in interactions characteristic to each. Therefore, depending on which aspects of the L-4'-phosphotyrosyl structure are emphasized, and the manner in which they are utilized, inhibitors can be potentially directed against distinct legs of the signalling triad. This review will provide examples of this, by examining several series of compounds that have been prepared as inhibitors of either PTKs, SH2/PTB domains or PTPs. Also described will be how the pTyr structure can serve as a thematic Rosetta stone for the development of signal transduction inhibitors.

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