title: Chemical tuning enhances both potency toward nrf2 and in vitro therapeutic index of triterpenoids.
abstract: 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.
authors.affiliation: 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.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Copple
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK.
authors.forename: Luke M
authors.initials: LM
authors.lastname: Shelton
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Walsh
authors.affiliation: Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Denise V
authors.initials: DV
authors.lastname: Kratschmar
authors.affiliation: Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Adam
authors.initials: A
authors.lastname: Lister
authors.affiliation: Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Alex
authors.initials: A
authors.lastname: Odermatt
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Goldring
authors.affiliation: Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee DD1 9SY, UK.
authors.forename: Albena T
authors.initials: AT
authors.lastname: Dinkova-Kostova
authors.affiliation: Department of Chemistry and Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, New York 11794.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Honda
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK.
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D051381:Rats; D014315:Triterpenes / Q000627:therapeutic use*
chemical_list: D051267:NF-E2-Related Factor 2; D014315:Triterpenes
keywords: Nrf2; therapeutic index; triterpenoids