Inhibitors for Proteins Endowed with Catalytic and Non-Catalytic Activity which Recognize pTyr

Abstract

Reversible phosphorylation of Tyr residues in proteins plays a central role in the transduction of signals. For both SH2 domains and for protein tyrosine phosphatases (PTPs) the phosphate group of phosphotyrosine (pTyr) of peptides provides a key affinity element, but its highly charged nature and its hydrolytic lability render it unsuitable in inhibitor design. The research in the recent years has been addressed to find pTyr bioisosters devoid of the phenylphosphate moiety and more potent inhibitors with less peptidic character. Several derivatives were prepared as pTyr bioisosters, and their activity appears to depend on the nature of the substrate, peptidic or low-molecular weight compounds, in which they are placed. In the field of PTPs, the research was mainly focused on new and selective PTP1B inhibitors, possibly useful in the treatment of Type 2 diabetes. The discovery of non-peptidic low molecular weight compounds able to inhibit PTP1B, by means of docking procedures and HTS screening, and the presence of secondary binding sites on PTP1B afforded new potent and selective inhibitors; several leads devoid of negative charges were also found. To date, however, few compounds have been tested In vivo and found to show a significant activity in diabetic mouse models. Other neutral compounds, mainly quinones, were found to inhibit CD45 and Cdc25. Several papers have appeared in recent years on the discovery of new Grb2, Src, Syk, and Lck SH2 domains binding antagonists. In this field very good inhibitors derived from high affinity peptides were found, with less peptidic character and with a reduced number of negative charges; however the presence of some negative charges, especially the one present on the pTyr bioisoster moiety, seems to be indispensable. As regards Grb2, Src and Lck SH2 domains, rigidification of the starting high affinity binding peptides afforded derivatives with improved affinity; cellular activity was achieved by modification of the side chains of these inhibitors.