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Author Spotlight: Developing Tools to Tune the Activity of Tyrosine Phosphatases
06:56

Author Spotlight: Developing Tools to Tune the Activity of Tyrosine Phosphatases

Published on: September 6, 2024

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Inhibition of Low Molecular Weight Protein Tyrosine Phosphatase by an Induced-Fit Mechanism

Rongjun He1, Jifeng Wang1, Zhi-Hong Yu1

  • 1Department of Medicinal Chemistry and Molecular Pharmacology, Department of Chemistry, Center for Cancer Research, and Institute for Drug Discovery, Purdue University , 720 Clinic Drive, West Lafayette, Indiana 47907, United States.

Journal of Medicinal Chemistry
|September 28, 2016
PubMed

Insights

Researchers discovered novel sulfophenyl acetic amide (SPAA) inhibitors targeting low molecular weight protein tyrosine phosphatase (LMW-PTP). These inhibitors show high selectivity, offering potential for oncology and diabetes treatments.

Area of Science:

  • Biochemistry
  • Enzymology
  • Drug Discovery

Background:

  • Low molecular weight protein tyrosine phosphatase (LMW-PTP) regulates critical signaling pathways.
  • LMW-PTP is a potential therapeutic target for oncology and diabetes/obesity.
  • Development of potent and selective LMW-PTP inhibitors is of significant therapeutic interest.

Purpose of the Study:

  • To discover and characterize novel inhibitors of LMW-PTP.
  • To investigate the structural basis for inhibitor selectivity.

Main Methods:

  • Synthesis of sulfophenyl acetic amide (SPAA)-based compounds.
  • Enzyme inhibition assays against LMW-PTP and a panel of other protein tyrosine phosphatases (PTPs).
  • X-ray crystallography to determine the binding mode of inhibitors.

Main Results:

  • Discovery of a novel class of SPAA-derived LMW-PTP inhibitors.
  • Some SPAA inhibitors demonstrated >50-fold selectivity for LMW-PTP over other PTPs.
  • X-ray crystallography revealed an induced-fit mechanism involving a novel hydrophobic pocket.

Conclusions:

  • SPAA-based compounds represent a promising new class of selective LMW-PTP inhibitors.
  • The observed induced-fit mechanism explains the high selectivity of these inhibitors.
  • These findings support the therapeutic potential of LMW-PTP inhibitors in cancer and metabolic diseases.

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