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Potent and selective inhibitors of glutathione S-transferase omega 1 that impair cancer drug resistance

Academic Article
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Overview

related to degree

  • Bachovchin, Daniel A., Ph.D. in Chemistry, Scripps Research 2006 - 2011

authors

  • Tsuboi, K.
  • Bachovchin, Daniel A.
  • Speers, Anna
  • Spicer, Timothy
  • Fernandez-Vega, V.
  • Hodder, Peter
  • Rosen, Hugh
  • Cravatt, Benjamin

publication date

  • October 2011

journal

  • Journal of the American Chemical Society  Journal

abstract

  • Glutathione S-transferases (GSTs) are a superfamily of enzymes that conjugate glutathione to a wide variety of both exogenous and endogenous compounds for biotransformation and/or removal. Glutathione S-tranferase omega 1 (GSTO1) is highly expressed in human cancer cells, where it has been suggested to play a role in detoxification of chemotherapeutic agents. Selective inhibitors of GSTO1 are, however, required to test the role that this enzyme plays in cancer and other (patho)physiological processes. With this goal in mind, we performed a fluorescence polarization activity-based protein profiling (fluopol-ABPP) high-throughput screen (HTS) with GSTO1 and the Molecular Libraries Small Molecule Repository (MLSMR) 300K+ compound library. This screen identified a class of selective and irreversible α-chloroacetamide inhibitors of GSTO1, which were optimized to generate an agent KT53 that inactivates GSTO1 with excellent in vitro (IC(50) = 21 nM) and in situ (IC(50) = 35 nM) potency. Cancer cells treated with KT53 show heightened sensitivity to the cytotoxic effects of cisplatin, supporting a role for GSTO1 in chemotherapy resistance.

subject areas

  • Antineoplastic Agents
  • Cell Proliferation
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors
  • Glutathione Transferase
  • Humans
  • Molecular Structure
  • Recombinant Proteins
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tumor Cells, Cultured
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Identity

PubMed Central ID

  • PMC3226709

International Standard Serial Number (ISSN)

  • 0002-7863

Digital Object Identifier (DOI)

  • 10.1021/ja2066972

PubMed ID

  • 21899313
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Additional Document Info

start page

  • 16605

end page

  • 16616

volume

  • 133

issue

  • 41

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