Cellular Inhibition of Protein Tyrosine Phosphatase 1B by Uncharged Thioxothiazolidinone Derivatives

• Published in: Chembiochem : a European journal of chemical biology 2007-01, Vol.8 (2), p.179-186
• Main Authors: Stuible, Matthew, Zhao, Liang, Aubry, Isabelle, Schmidt-Arras, Dirk, Böhmer, Frank-D., Li, Chao-Jun, Tremblay, Michel L.
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Enzyme Activation - drug effects; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; enzymes; inhibitors; Kinetics; Mice; Models, Molecular; Molecular Structure; Oxygen - chemistry; Protein Binding; Protein Structure, Tertiary; Protein Tyrosine Phosphatase, Non-Receptor Type 1; protein tyrosine phosphatases; Protein Tyrosine Phosphatases - antagonists & inhibitors; Protein Tyrosine Phosphatases - chemistry; Protein Tyrosine Phosphatases - genetics; Protein Tyrosine Phosphatases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; PTP1B; Structure-Activity Relationship; Sulfhydryl Compounds - chemistry; Thiazolidines - chemistry; Thiazolidines - pharmacology; thioxothiazolidinone
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.200600287

As important regulators of cellular signal transduction, members of the protein tyrosine phosphatase (PTP) family are considered to be promising drug targets. However, to date, the most effective in vitro PTP inhibitors have tended to be highly charged, thus limiting cellular permeability. Here, we have identified an uncharged thioxothiazolidinone derivative (compound 1), as a competitive inhibitor of a subset of PTPs. Compound 1 effectively inhibited protein tyrosine phosphatase 1B (PTP1B) in two cell‐based systems: it sensitized wild‐type, but not PTP1B‐null fibroblasts to insulin stimulation and prevented PTP1B‐dependent dephosphorylation of the FLT3‐ITD receptor tyrosine kinase. We have also tested a series of derivatives in vitro against PTP1B and proposed a model of the PTP1B–inhibitor interaction. These compounds should be useful in the elucidation of cellular PTP function and could represent a starting point for development of therapeutic PTP inhibitors. Charge less. We show that a novel inhibitor (1) of PTP1B is active in cells at low micromolar concentrations and prevents PTP1B‐mediated dephosphorylation of the FLT3‐ITD receptor tyrosine kinase (shown). We have synthesized a series of derivatives for basic SAR analysis and have conducted computer‐modeling studies to predict its binding mode. This class of uncharged inhibitors could be a starting point for the development of new drugs targeting protein tyrosine phosphatases.