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ENOblock Does Not Inhibit the Activity of the Glycolytic Enzyme Enolase.

Inhibition of glycolysis is of great potential for the treatment of cancer. However, inhibitors of glycolytic enzymes with favorable pharmacological profiles have not been forthcoming. Due to the nature of their active sites, most high-affinity transition-state analogue inhibitors of glycolysis enzy... Full description

Journal Title: PloS one 2016, Vol.11(12), p.e0168739
Main Author: Satani, Nikunj
Other Authors: Lin, Yu-Hsi , Hammoudi, Naima , Raghavan, Sudhir , Georgiou, Dimitra K , Muller, Florian L
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1932-6203 ; DOI: 10.1371/journal.pone.0168739
Link: http://search.proquest.com/docview/1854105083/?pq-origsite=primo
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title: ENOblock Does Not Inhibit the Activity of the Glycolytic Enzyme Enolase.
format: Article
creator:
  • Satani, Nikunj
  • Lin, Yu-Hsi
  • Hammoudi, Naima
  • Raghavan, Sudhir
  • Georgiou, Dimitra K
  • Muller, Florian L
subjects:
  • Benzamides–Pharmacology
  • Cell Line, Tumor–Antagonists & Inhibitors
  • Glycolysis–Metabolism
  • Humans–Pharmacology
  • Phosphopyruvate Hydratase–Pharmacology
  • Triazines–Pharmacology
  • Benzamides
  • Enoblock
  • Triazines
  • Phosphopyruvate Hydratase
ispartof: PloS one, 2016, Vol.11(12), p.e0168739
description: Inhibition of glycolysis is of great potential for the treatment of cancer. However, inhibitors of glycolytic enzymes with favorable pharmacological profiles have not been forthcoming. Due to the nature of their active sites, most high-affinity transition-state analogue inhibitors of glycolysis enzymes are highly polar with poor cell permeability. A recent publication reported a novel, non-active site inhibitor of the glycolytic enzyme Enolase, termed ENOblock (N-[2-[2-2-aminoethoxy)ethoxy]ethyl]4-4-cyclohexylmethyl)amino]6-4-fluorophenyl)methyl]amino]1,3,5-triazin-2-yl]amino]benzeneacetamide). This would present a major advance, as this is heterocyclic and fully cell permeable molecule. Here, we present evidence that ENOblock does not inhibit Enolase enzymatic activity in vitro as measured by three different assays, including a novel .sup.31 P NMR based method which avoids complications associated with optical interferences in the UV range. Indeed, we note that due to strong UV absorbance, ENOblock interferes with the direct spectrophotometric detection of the product of Enolase, phosphoenolpyruvate. Unlike established Enolase inhibitors, ENOblock does not show selective toxicity to ENO1-deleted glioma cells in culture. While our data do not dispute the biological effects previously attributed to ENOblock, they indicate that such effects must be caused by mechanisms other than direct inhibition of Enolase enzymatic activity.
language: eng
source:
identifier: E-ISSN: 1932-6203 ; DOI: 10.1371/journal.pone.0168739
fulltext: fulltext
issn:
  • 19326203
  • 1932-6203
url: Link


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titleENOblock Does Not Inhibit the Activity of the Glycolytic Enzyme Enolase.
creatorSatani, Nikunj ; Lin, Yu-Hsi ; Hammoudi, Naima ; Raghavan, Sudhir ; Georgiou, Dimitra K ; Muller, Florian L
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identifierE-ISSN: 1932-6203 ; DOI: 10.1371/journal.pone.0168739
subjectBenzamides–Pharmacology ; Cell Line, Tumor–Antagonists & Inhibitors ; Glycolysis–Metabolism ; Humans–Pharmacology ; Phosphopyruvate Hydratase–Pharmacology ; Triazines–Pharmacology ; Benzamides ; Enoblock ; Triazines ; Phosphopyruvate Hydratase
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descriptionInhibition of glycolysis is of great potential for the treatment of cancer. However, inhibitors of glycolytic enzymes with favorable pharmacological profiles have not been forthcoming. Due to the nature of their active sites, most high-affinity transition-state analogue inhibitors of glycolysis enzymes are highly polar with poor cell permeability. A recent publication reported a novel, non-active site inhibitor of the glycolytic enzyme Enolase, termed ENOblock (N-[2-[2-2-aminoethoxy)ethoxy]ethyl]4-4-cyclohexylmethyl)amino]6-4-fluorophenyl)methyl]amino]1,3,5-triazin-2-yl]amino]benzeneacetamide). This would present a major advance, as this is heterocyclic and fully cell permeable molecule. Here, we present evidence that ENOblock does not inhibit Enolase enzymatic activity in vitro as measured by three different assays, including a novel .sup.31 P NMR based method which avoids complications associated with optical interferences in the UV range. Indeed, we note that due to strong UV absorbance, ENOblock interferes with the direct spectrophotometric detection of the product of Enolase, phosphoenolpyruvate. Unlike established Enolase inhibitors, ENOblock does not show selective toxicity to ENO1-deleted glioma cells in culture. While our data do not dispute the biological effects previously attributed to ENOblock, they indicate that such effects must be caused by mechanisms other than direct inhibition of Enolase enzymatic activity.
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titleENOblock Does Not Inhibit the Activity of the Glycolytic Enzyme Enolase.
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