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J Biol Chem, Vol. 275, Issue 10, 7101-7108, March 10, 2000

2-(Oxalylamino)-Benzoic Acid Is a General, Competitive Inhibitor of Protein-tyrosine Phosphatases*

Henrik Sune AndersenDagger §, Lars Fogh Iversen||, Claus Bekker Jeppesen**, Sven Branner||, Kjeld NorrisDagger Dagger , Hanne B. Rasmussen||, Karin Bach Møller§§, and Niels Peter Hundahl Møller§§

From Dagger  MedChem Research I, || Protein Chemistry, ** New Lead Discovery, Dagger Dagger  Diabetes Biology, and §§ Signal Transduction, Novo Nordisk, DK-2880 Bagsvaerd, Denmark

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 Asp181, Lys120, and Tyr46. 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.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: Signal Transduction, Bldg. 6A1.086, Novo Nordisk, Novo Alle, DK-2880 Bagsvaerd, Denmark. Tel.: 45-4442-2899; Fax: 45-4442-7484 E-mail: nphm@novo.dk or hsa{at}novo.dk.

Contributed equally to this report.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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