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Chemical tuning enhances both potency toward nrf2 and in vitro therapeutic index of triterpenoids.

  • Copple IM MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK ian.copple@liv.ac.uk.
  • Shelton LM MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK.
  • Walsh J MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK.
  • Kratschmar DV Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, CH-4056 Basel, Switzerland.
  • Lister A Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, CH-4056 Basel, Switzerland.
  • Odermatt A Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, CH-4056 Basel, Switzerland.
  • Goldring CE MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK.
  • Dinkova-Kostova AT Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee DD1 9SY, UK.
  • Honda T Department of Chemistry and Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, New York 11794.
  • Park BK MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK.
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  • 2014-05-07
Published in:
  • Toxicological sciences : an official journal of the Society of Toxicology. - 2014
Nrf2
therapeutic index
triterpenoids
Animals
Cell Line
Humans
In Vitro Techniques
Mice
NF-E2-Related Factor 2
Rats
Triterpenes
English The transcription factor Nrf2 protects against a number of experimental pathologies, and is a promising therapeutic target. The clinical investigation of a potent Nrf2-inducing agent, the triterpenoid (TP) bardoxolone methyl (BARD), was recently halted due to adverse cardiovascular events in chronic kidney disease patients, although the underlying mechanisms are yet to be resolved. The majority of small molecule Nrf2 inducers are electrophilic and trigger Nrf2 accumulation via the chemical modification of its redox-sensitive repressor Keap1. Therefore, it is pertinent to question whether the therapeutic targeting of Nrf2 could be hindered in many cases by the inherent reactivity of a small molecule inducer toward unintended cellular targets, a key mechanism of drug toxicity. Using H4IIE-ARE8L hepatoma cells, we have examined the relationship between (a) Nrf2 induction potency, (b) toxicity and (c) in vitro therapeutic index (ratio of b:a) for BARD and a number of other small molecule activators of Nrf2. We show that BARD exhibits the highest potency toward Nrf2 and the largest in vitro therapeutic index among compounds that have been investigated clinically (namely BARD, sulforaphane and dimethylfumarate). Through further examination of structurally related TPs, we demonstrate that an increase in potency toward Nrf2 is associated with a relatively smaller increase in toxicity, indicating that medicinal chemistry can be used to enhance the specificity of a compound as an inducer of Nrf2 signaling whilst simultaneously increasing its therapeutic index. These findings will inform the continuing design and development of drugs targeting Nrf2.
Language
  • English
Open access status
hybrid
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Persistent URL
https://folia.unifr.ch/global/documents/111052
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