2-(Oxalylamino)-benzoic acid is a general, competitive inhibitor of protein-tyrosine phosphatases

Protein-tyrosine phosphatases (PTPs) are critically involved in regulation of signal transduction processes. Members of this class of enzymes are cons idered attractive therapeutic targets in several disease states, e.g. diabe tes, cancer, and inflammation. However, most reported PTP inhibitors have b een phosphorus-containing compounds, tight binding inhibitors, and/or inhib itors that covalently modify the enzymes. We therefore embarked on identify ing a general, reversible, competitive PTP inhibitor that could be used as a common scaffold for lead optimization for specific PTPs, We here report t he identification of 2-(oxalylamino)-benzoic acid (OBA) as a classical comp etitive inhibitor of several PTPs, X-ray crystallography of PTP1B complexed with OBA and related non-phosphate low molecular weight derivatives reveal s that the binding mode of these molecules to a large extent mimics that of the natural substrate including hydrogen bonding to the PTP signature moti f, In addition, binding of OBA to the active site of PTP1B creates a unique arrangement involving Asp(181), Lys(120), and Tyr(46). PTP inhibitors are essential tools in elucidating the biological function of specific PTPs and they may eventually be developed into selective drug candidates, The uniqu e enzyme kinetic features and the low molecular weight of OBA makes it an i deal starting point for further optimization.