Selective protein tyrosine phosphatase 1B inhibitors: targeting the second phosphotyrosine binding site with non-carboxylic acid-containing ligands

J Med Chem. 2003 Jul 31;46(16):3437-40. doi: 10.1021/jm034088d.

Abstract

Protein tyrosine phosphatase (PTPase) 1B (PTP1B) has been implicated as a key negative regulator of both insulin and leptin signaling cascades. We identified several salicylic acid-based ligands for the second phosphotyrosine binding site of PTP1B using a NMR-based screening. Structure-based linking with a catalytic site-directed oxalylarylaminobenzoic acid-based pharmacophore led to the identification of a novel series of potent PTP1B inhibitors exhibiting 6-fold selectivity over the highly homologous T-cell PTPase (TCPTP) and high selectivity over other phosphatases.

MeSH terms

  • Catalytic Domain
  • Combinatorial Chemistry Techniques
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Phosphotyrosine / chemistry*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatases / antagonists & inhibitors*
  • Protein Tyrosine Phosphatases / chemistry
  • Salicylates / chemical synthesis*
  • Salicylates / chemistry
  • Stereoisomerism
  • Structure-Activity Relationship
  • T-Lymphocytes / chemistry

Substances

  • Enzyme Inhibitors
  • Ligands
  • Salicylates
  • Phosphotyrosine
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatases