[Difluro(phosphono)methyl]phenylalanine-containing peptide inhibitors of protein tyrosine phosphatases

Peptides containing the non-hydrolysable phosphotyrosine analogue 4-[difluro(phosphono)methyl]phenylalanine [Phe(CF 2 P )] were synthesized and tested as inhibitors of the protein tyrosine phosphatases (PTPs) PTP1B, CD45, PTPβ, LAR and SHP-1. We have identified peptides containing two adjacent Phe(CF 2 P ) residues as potent inhibitors of PTPs. The tripeptide having the sequence Glu-Phe(CF 2 P )-Phe(CF 2 P ) is a potent and selective inhibitor of PTP1B. This peptide inhibits PTP1B with an IC 50 of 40 nM, which is at least 100-fold lower than with other PTPs. A second tripeptide, Pro-Phe(CF 2 P )-Phe(CF 2 P ), is most potent against PTPβ, with an IC 50 of 200 nM, and inhibits PTP1B with an IC 50 of 300 nM. These data suggest that it is possible to develop selective, active-site-directed, reversible, potent inhibitors of PTPs.