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Profiling Thiol Redox Proteome Using Isotope Tagging Mass Spectrometry
12:07

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Published on: March 24, 2012

Redox active disulfides: the thioredoxin system as a drug target

D L Kirkpatrick1, G Ehrmantraut, S Stettner

  • 1Department of Chemistry, University of Regina, Canada. kirkpaly@leroy.cc.uregina.ca

Oncology Research
|January 1, 1997
PubMed

Insights

Novel disulfide compounds show promise as cancer treatments by inhibiting the thioredoxin system. One compound, IV-2, selectively targets tumor cell growth and demonstrates antitumor activity in vivo.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Oncology

Background:

  • Extracellular thioredoxin is a potential target for novel cancer therapies.
  • Alkyl 2-imidazolyl disulfides were investigated as inhibitors of the thioredoxin system.

Purpose of the Study:

  • To develop and evaluate novel alkyl 2-imidazolyl disulfides as inhibitors of thioredoxin.
  • To identify specific inhibitors of the thioredoxin system for potential anticancer drug development.

Main Methods:

  • Synthesis of a library of alkyl 2-imidazolyl disulfide analogues using a parallel combinatorial method.
  • Evaluation of biological activity of synthesized analogues in a 96-well plate format.
  • Assessment of selective inhibition of thioredoxin-dependent tumor cell growth and in vivo antitumor activity.

Main Results:

  • Alkyl 2-imidazolyl disulfides were found to interact directly with thioredoxin, leading to loss of biological activity.
  • The analogue 1-methylpropyl 2-imidazolyl disulfide (IV-2) selectively inhibited thioredoxin-dependent tumor cell growth.
  • IV-2 demonstrated significant antitumor activity against MCF-7 and HL-60 tumors in vivo.

Conclusions:

  • Alkyl 2-imidazolyl disulfides are effective inhibitors of the thioredoxin system.
  • IV-2 shows potential as a novel antitumor agent for solid tumor cancers.
  • A high-throughput screening method facilitates the identification of specific thioredoxin system inhibitors.

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