title: 2-(oxalylamino)-benzoic acid is a general, competitive inhibitor of protein-tyrosine phosphatases.
abstract: Protein-tyrosine phosphatases (PTPs) are critically involved in regulation of signal transduction processes. Members of this class of enzymes are considered attractive therapeutic targets in several disease states, e.g. diabetes, cancer, and inflammation. However, most reported PTP inhibitors have been phosphorus-containing compounds, tight binding inhibitors, and/or inhibitors that covalently modify the enzymes. We therefore embarked on identifying a general, reversible, competitive PTP inhibitor that could be used as a common scaffold for lead optimization for specific PTPs. We here report the identification of 2-(oxalylamino)-benzoic acid (OBA) as a classical competitive inhibitor of several PTPs. X-ray crystallography of PTP1B complexed with OBA and related non-phosphate low molecular weight derivatives reveals that the binding mode of these molecules to a large extent mimics that of the natural substrate including hydrogen bonding to the PTP signature motif. 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 unique enzyme kinetic features and the low molecular weight of OBA makes it an ideal starting point for further optimization.
authors.affiliation: MedChem Research I, Novo Nordisk, DK-2880 Bagsvaerd, Denmark. hsa@novo.dk
authors.forename: H S
authors.initials: HS
authors.lastname: Andersen
authors.forename: L F
authors.initials: LF
authors.lastname: Iversen
authors.forename: C B
authors.initials: CB
authors.lastname: Jeppesen
authors.forename: S
authors.initials: S
authors.lastname: Branner
authors.forename: K
authors.initials: K
authors.lastname: Norris
authors.forename: H B
authors.initials: HB
authors.lastname: Rasmussen
authors.forename: K B
authors.initials: KB
authors.lastname: Møller
authors.forename: N P
authors.initials: NP
authors.lastname: Møller
mesh_terms: D001665:Binding Sites; D002384:Catalysis; D003460:Crystallization; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D010070:Oxalates / Q000494:pharmacology*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013997:Time Factors; D014961:X-Ray Diffraction; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
chemical_list: C405943:2-(oxalylamino)benzoic acid; D004791:Enzyme Inhibitors; D010070:Oxalates; D062367:ortho-Aminobenzoates; D017027:Protein Tyrosine Phosphatases