Nrf2 activation through the inhibition of Keap1–Nrf2 protein–protein interaction

Sumi Lee, Longqin Hu

Research output: Contribution to journalReview articlepeer-review

35 Scopus citations


Activation of the transcription factor Nrf2 via the Keap1–Nrf2–ARE signaling system regulates the transcription and subsequent expression of cellular cytoprotective proteins and plays a crucial role in preventing pathological conditions exacerbated by the overproduction of oxidative stress. In addition to electrophilic modulators, direct noncovalent inhibitors that interrupt the Keap1–Nrf2 protein–protein interaction (PPI) leading to Nrf2 activation have attracted a great deal of attention as potential preventive and therapeutic agents for oxidative stress-related diseases. Structural studies of Keap1-binding ligands, development of biochemical and cellular assays, and new structure-based design approaches have facilitated the discovery of small molecule PPI inhibitors. This perspective reviews the Keap1–Nrf2–ARE system, its physiological functions, and the recent progress in the discovery and the potential applications of direct inhibitors of Keap1–Nrf2 PPI. [Figure not available: see fulltext.]

Original languageEnglish (US)
Pages (from-to)846-867
Number of pages22
JournalMedicinal Chemistry Research
Issue number5
StatePublished - May 1 2020

All Science Journal Classification (ASJC) codes

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry


  • Keap1
  • Keap1–Nrf2 interaction
  • Nrf2
  • Oxidative stress
  • Protein–protein interaction Inhibitor
  • Structure–activity relationship


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