The α,α-Difluorinated Phosphonate L-pSer-Analogue: An Accessible Chemical Tool for Studying Kinase- Dependent Signal Transduction Review Article

This overview focuses on the (α,α-difluoromethylene)phosphonate mimic of phosphoserine (pCF2Ser) and its application to the study of kinase-mediated signal transduction—pathways of great interest to drug development. The most versatile modes of access to these chemical biological tools are discussed, organized by method of PCF2-C bond formation. The pCF2-Ser mimic may be site-specifically incorporated into peptides (SPPS) and proteins (expressed protein ligation). This isopolar, dianionic pSer mimic results in a “constitutive phosphorylation” phenotype and is seen to support native protein-protein interactions that depend on serine phosphorylation. Signal transduction pathways studied with this chemical biological approach include the regulation of p53 tumor suppressor protein activity and of melatonin production. Given these successes, the future is bright for the use of such “teflon phospho-amino acid mimics” to map kinase-based signaling pathways.