POTENT NON-PEPTIDYL INHIBITORS OF PROTEIN-TYROSINE-PHOSPHATASE 1B

The development of inhibitors of protein tyrosine phosphatases (PTPs) has recently been the subject of intensive investigation due to their potential as chemotherapeutics and as tools for studying signal transd uction pathways. Here we report the evaluation of a variety of small m olecule, non-peptidyl inhibitors of protein tyrosine phosphatase 1B (P TP1B), bearing the alpha,alpha-difluoromethylenephosphonic acid (DFMP) group, a non-hydrolyzable phosphate mimetic. A series of phenyl deriv atives bearing a single DFMP group were initially surveyed. In general , these were not significantly more potent inhibitors than the parent compound, alpha,alpha-difluorobenzylphosphonic acid, with the exceptio n being the meta-phenyl substituted species which decreased the IC50 b y approximately 17-fold relative to alpha,alpha-difluorobenzylphosphon ic acid. However, certain compounds bearing two DFMP moieties were ver y potent inhibitors. Some of these are among the most potent small mol ecule inhibitors of any PTP reported to date with the best one exhibit ing a K-i of 1.5 mu M. The structural basis for these results are disc ussed. One of the bis-DFMP inhibitors was examined in detail and it wa s found that the fluorines were essential for potent inhibition. Inhib ition was independent of pH between pH 5.5-7.2 suggesting that both th e mono and dianionic forms of the individual DFMP groups bind equally well. The trends observed in the inhibitory potency of these compounds with PTP1B were very similar to the trends observed by other workers on the K-m's of the analogous phenylphosphate substrates with rat PTP1 . This indicates that studies of non-peptidyl substrates with rat PTP1 can be used as a guide for the development of human PTP1B inhibitors. (C) 1998 Elsevier Science Ltd. All rights reserved.