Phosphotyrosyl Mimetics in the Development of Signal Transduction Inhibitors

Phosphotyrosyl (pTyr) residues play important roles in cellular signal transduction by facilitating recognition and binding necessary for critical protein-protein interactions, and for this reason pTyr motifs represent attractive starting points in the development of signaling antagonists. Although the pTyr phosphoryl moiety is central in these phenomena, its incorporation into signaling inhibitors is contraindicated due to enzymatic lability and limited bioavailability associated with phosphate esters. To address these limitations, an entire field of study has arisen devoted to the design and utilization of pTyr mimetics. This Account provides a perspective on the roles of pTyr residues in signal transduction and approaches to pTyr mimetic development.