Discovery of a novel competitive inhibitor of PTP1B by high-throughput screening

Acta Pharmacol Sin. 2008 Feb;29(2):278-84. doi: 10.1111/j.1745-7254.2008.00737.x.

Abstract

Aim: The aim of the present study was to discover novel protein tyrosine phosphatase 1B (PTP1B) inhibitors. We expressed and purified the human PTP1B catalytic domain and set up a molecular level high-throughput screening (HTS) assay to screen a set of 48,000 pure compounds.

Results: HTS was finished with an averaged Zo factor of 0.63, and LGH00081, a competitive inhibitor of PTP1B with novel structure and relatively good selectivity for receptor-type protein tyrosine phosphatases, was identified.

Conclusion: We established a molecular level assay which is useful for the screening of PTP1B inhibitors with therapeutic potential. The novel competitive PTP1B inhibitor LGH00081 offers a good start for structure modification and cellular functional activity study.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Catalysis
  • Cricetinae
  • Cricetulus
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / chemistry
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / genetics
  • Tyrosine / metabolism

Substances

  • Enzyme Inhibitors
  • Tyrosine
  • PTPN1 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1