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Isozyme specificity of novel glutathione-S-transferase inhibitors

  • Original Articles
  • Gluthatione-S-Transferase, Isozyme Selectivity, Paralog Inhibition
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Abstract

A systematically diversified set of peptide analogs of the reaction product of glutathione with an electrophilic substrate have been tested as isozyme-specific inhibitors of human glutathione-S-transferase (GST). The potency of the best of the inhibitors is in the 0.5 to 20 micromolar range, with kinetics indicative of competitive inhibition with glutathione at the active site. The specificity observed among three recombinant-derived GST isozymes at both low and high potency ranged from negligible to high (at least 20-fold over the next most sensitive isozyme). These results define a novel strategy for the design of drugs targeting cells with elevated levels of particular GST isozymes, such as tumor cells for which elevated levels of GST are believed to be an important cause of chemotherapeutic drug resistance.

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Abbreviations

GSH:

glutathione

GST:

glutathione-S-transferase

CDNB:

1-chloro-2,4-dinitrobenzene

phegly:

S(+)phenylglycine

β-ala:

3-aminopropionic acid

4-ABu:

4-aminobutyric acid

QSAR:

quantitative structure/activity relationship

IC50 :

concentration required for 50% inhibition

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Authors and Affiliations

  1. Terrapin Technologies, Inc., 750-H Gateway Boulevard, 94080, South San Francisco, CA, USA

    Jeffrey E. Flatgaard, Karin E. Bauer & Lawrence M. Kauvar

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  1. Jeffrey E. Flatgaard
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  2. Karin E. Bauer
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  3. Lawrence M. Kauvar
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Flatgaard, J.E., Bauer, K.E. & Kauvar, L.M. Isozyme specificity of novel glutathione-S-transferase inhibitors. Cancer Chemother. Pharmacol. 33, 63–70 (1993). https://doi.org/10.1007/BF00686025

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  • DOI: https://doi.org/10.1007/BF00686025

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