Phosphoryltyrosyl mimetics in the design of peptide-based signal transduction inhibitors

The central roles played by protein-tyrosine kinase (PTK)-dependent signal transduction in normal cellular regulation and homeostasis have made inappr opriate or aberrant functions of certain of these pathways contributing fac tors to a variety of diseases, including several cancers. For this reason, development of PTK signaling inhibitors has evolved into an important appro ach toward new therapeutics. Since in these pathways phosphotyrosyl (pTyr) residues provide unique and defining functions either by their creation und er the catalysis of PTKs, their recognition and binding by protein modules such as SH2 and phosphotyrosyl binding (PTB) domains, or their destruction by protein-tyrosine phosphatases, pTyr mimetics provide useful general star ting points for inhibitor design. Important considerations in the developme nt of such pTyr mimetics include enzymatic stability (particularly toward P TPs), high affinity recognition by target pTyr binding proteins, and good c ellular bioavailability. Although small molecule, nonpeptide inhibitors may be ultimate objectives of inhibitor development, peptides frequently serve as display platforms for pTyr mimetics, which afford useful and conceptual ly straightforward starting paints in the development process. Reported her ein is a limited overview of pTyr mimetic development as it relates to pept ide-based agents. Of particular interest are recent findings that highlight potential limitations of peptides as display platforms for the identificat ion of small molecule lends. One conclusion that results from this work is that while peptide-based approaches toward small molecule inhibitor design are often intellectually satisfying fr-om a structure-based perspective, ex trapolation of negative findings to small molecule, nonpeptide contexts sho uld be undertaken with extreme caution. (C) 2001 John Wiley & Sons, Inc.*