Phenyl Bis-Sulfonamide Keap1-Nrf2 Protein-Protein Interaction Inhibitors with an Alternative Binding Mode

Nikolaos Georgakopoulos, Sandeep Talapatra, Dina Dikovskaya, Sharadha Dayalan Naidu, Maureen Higgins, Jemma Gatliff, Aysel Ayhan, Roxani Nikoloudaki, Marjolein Schaap, Klara Valko, Farideh Javid, Albena T. Dinkova-Kostova, Frank Kozielski, Geoffrey Wells (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)
120 Downloads (Pure)


Inhibitors of Kelch-like ECH-associated protein 1 (Keap1) increase the activity of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) by stalling its ubiquitination and degradation. This enhances the expression of genes encoding proteins involved in drug detoxification, redox homeostasis, and mitochondrial function. Nrf2 activation offers a potential therapeutic approach for conditions including Alzheimer's and Parkinson's diseases, vascular inflammation, and chronic obstructive airway disease. Non-electrophilic Keap1-Nrf2 protein-protein interaction (PPI) inhibitors may have improved toxicity profiles and different pharmacological properties to cysteine-reactive electrophilic inhibitors. Here, we describe and characterize a series of phenyl bis-sulfonamide PPI inhibitors that bind to Keap1 at submicromolar concentrations. Structural studies reveal that the compounds bind to Keap1 in a distinct "peptidomimetic" conformation that resembles the Keap1-Nrf2 ETGE peptide complex. This is different to other small molecule Keap1-Nrf2 PPI inhibitors, including bicyclic aryl bis-sulfonamides, offering a starting point for new design approaches to Keap1 inhibitors.

Original languageEnglish
Pages (from-to)7380-7398
Number of pages19
JournalJournal of Medicinal Chemistry
Issue number10
Early online date12 May 2022
Publication statusPublished - 26 May 2022


  • Assays
  • High-performance liquid chromatography
  • Inhibitors
  • Screening assays

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine


Dive into the research topics of 'Phenyl Bis-Sulfonamide Keap1-Nrf2 Protein-Protein Interaction Inhibitors with an Alternative Binding Mode'. Together they form a unique fingerprint.

Cite this