The status of Nrf2-based therapeutics

Current perspectives and future prospects

Irina G. Gazaryan, Bobby Thomas

Research output: Contribution to journalReview article

19 Citations (Scopus)

Abstract

This mini-review presents the authors’ vision on the current status and future trends in the development of neuroprotective agents working via activation of nuclear factor erythroid 2-related factor 2 (Nrf2), and in particular, via disruption of Nrf2-Keap1 interaction. There are two opposite “chemical” mechanisms underlying such activation: the first one is a non-specific covalent modification of Keap1 thiols, resulting in side effects of varied severity, and the second one is the shift of the Nrf2-Kelch-like ECH associated protein-1 (Keap1) binding equilibrium in the presence of a competitive and chemically benign displacement agent. At this point, no displacement activators exhibit sufficient biological activity in comparison with common Nrf2 activators working via Keap1 thiol modification. Hence, the hope in therapeutics is now linked to the FDA approved dimethylfumarate, whose derivative, monomethylfumarate, as we demonstrated recently, is much less toxic but equally biologically potent and an ideal candidate for clinical trials right now. A newly emerging player is a nuclear inhibitor of Nrf2, BTB domain and CNC homolog 1 (Bach1). The commercially developed Bach1 inhibitors are currently under investigation in our laboratory showing promising results. In our viewpoint, the perfect future drug will present the combination of a displacement activator and Bach1 inhibitor to insure safety and efficiency of Nrf2 activation.

Original languageEnglish (US)
Pages (from-to)1708-1711
Number of pages4
JournalNeural Regeneration Research
Volume11
Issue number11
DOIs
StatePublished - Jan 1 2016

Fingerprint

Sulfhydryl Compounds
Poisons
Neuroprotective Agents
Therapeutics
Protein Binding
Clinical Trials
Safety
Kelch-Like ECH-Associated Protein 1
Pharmaceutical Preparations
BTB-POZ Domain
Dimethyl Fumarate
citraconic acid

Keywords

  • Antioxidants
  • Bach1
  • Electrophiles
  • Keap1
  • Nrf2
  • Oxidative stress

ASJC Scopus subject areas

  • Developmental Neuroscience

Cite this

The status of Nrf2-based therapeutics : Current perspectives and future prospects. / Gazaryan, Irina G.; Thomas, Bobby.

In: Neural Regeneration Research, Vol. 11, No. 11, 01.01.2016, p. 1708-1711.

Research output: Contribution to journalReview article

Gazaryan, Irina G. ; Thomas, Bobby. / The status of Nrf2-based therapeutics : Current perspectives and future prospects. In: Neural Regeneration Research. 2016 ; Vol. 11, No. 11. pp. 1708-1711.
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