Fragment screening and assembly: a highly efficient approach to a selective and cell active protein tyrosine phosphatase 1B inhibitor

J Med Chem. 2003 Sep 25;46(20):4232-5. doi: 10.1021/jm034122o.

Abstract

Using an NMR-based fragment screening and X-ray crystal structure-based assembly, starting with millimolar ligands for both the catalytic site and the second phosphotyrosine binding site, we have identified a small-molecule inhibitor of protein tyrosine phosphatase 1B with low micromolar inhibition constant, high selectivity (30-fold) over the highly homologous T-cell protein tyrosine phosphatase, and good cellular activity in COS-7 cells.

MeSH terms

  • Animals
  • Binding Sites
  • COS Cells
  • Catalytic Domain
  • Crystallography, X-Ray
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / metabolism
  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Models, Molecular
  • Molecular Mimicry
  • Nuclear Magnetic Resonance, Biomolecular / methods
  • Oxamic Acid / analogs & derivatives*
  • Oxamic Acid / chemical synthesis
  • Oxamic Acid / pharmacology*
  • Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2
  • Protein Tyrosine Phosphatases / antagonists & inhibitors*
  • Protein Tyrosine Phosphatases / metabolism
  • STAT3 Transcription Factor
  • Structure-Activity Relationship
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / metabolism

Substances

  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • STAT3 Transcription Factor
  • Trans-Activators
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2
  • Protein Tyrosine Phosphatases
  • Oxamic Acid