Discovery of Bisindole as a Novel Scaffold for Protein Tyrosine Phosphatase 1B Inhibitors

Arch Pharm (Weinheim). 2017 Jan;350(1). doi: 10.1002/ardp.201600173. Epub 2016 Dec 28.

Abstract

Protein tyrosine phosphatase 1B (PTP1B) has been proposed to be an effective target for the treatment of both type II diabetes and obesity. However, no PTP1B inhibitor has come into clinic application. Herein, we report mixed 3,3'-bisindoles as novel PTP1B inhibitors with low micromole-ranged inhibitory activity. The best active compound 9f inhibited PTP1B activity with an IC50 of 2.79 µM. Meanwhile, it had low cytotoxicity and enhanced glucose uptake in vitro. Further studies demonstrated that some of these active compounds had a specific selectivity over other PTPs. Computational analysis further showed the binding mode of compound 9f with the active pocket of PTP1B. Our studies provide a novel scaffold for further development of more promising PTP1B inhibitors and potential drugs for type II diabetes and obesity.

Keywords: Inhibitor; Mixed 3,3′-bisindoles; Molecular docking; Protein tyrosine phosphatase 1B.

MeSH terms

  • Animals
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Glucose / metabolism
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / pharmacology*
  • Mice
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Indoles
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Glucose