title: Structure-based design of selective and potent inhibitors of protein-tyrosine phosphatase beta.
abstract: Protein-tyrosine phosphatases (PTPs) are considered important therapeutic targets because of their pivotal role as regulators of signal transduction and thus their implication in several human diseases such as diabetes, cancer, and autoimmunity. In particular, PTP1B has been the focus of many academic and industrial laboratories because it was found to be an important negative regulator of insulin and leptin signaling, and hence a potential therapeutic target in diabetes and obesity. As a result, significant progress has been achieved in the design of highly selective and potent PTP1B inhibitors. In contrast, little attention has been given to other potential drug targets within the PTP family. Guided by x-ray crystallography, molecular modeling, and enzyme kinetic analyses with wild type and mutant PTPs, we describe the development of a general, low molecular weight, non-peptide, non-phosphorus PTP inhibitor into an inhibitor that displays more than 100-fold selectivity for PTPbeta over PTP1B. Of note, our structure-based design principles, which are based on extensive bioinformatics analyses of the PTP family, are general in nature. Therefore, we anticipate that this strategy, here applied to PTPbeta, in principle can be used in the design and development of selective inhibitors of many, if not most PTPs.
authors.affiliation: Signal Transduction, Protein Science, Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark.
authors.forename: Ida Katrine
authors.initials: IK
authors.lastname: Lund
authors.forename: Henrik Sune
authors.initials: HS
authors.lastname: Andersen
authors.forename: Lars Fogh
authors.initials: LF
authors.lastname: Iversen
authors.forename: Ole Hvilsted
authors.initials: OH
authors.lastname: Olsen
authors.forename: Karin Bach
authors.initials: KB
authors.lastname: Møller
authors.forename: Anja Kallesøe
authors.initials: AK
authors.lastname: Pedersen
authors.forename: Yu
authors.initials: Y
authors.lastname: Ge
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Holsworth
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Newman
authors.forename: Frank U
authors.initials: FU
authors.lastname: Axe
authors.forename: Niels Peter Hundahl
authors.initials: NP
authors.lastname: Møller
mesh_terms: D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D007328:Insulin / Q000378:metabolism; D007700:Kinetics; D020738:Leptin / Q000378:metabolism; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D009154:Mutation; D010797:Phthalimides / Q000737:chemistry; D011487:Protein Conformation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013696:Temperature
chemical_list: D004791:Enzyme Inhibitors; D007328:Insulin; D020738:Leptin; D008024:Ligands; D010797:Phthalimides; C037431:phthalimide; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases