2. Academic Validation
  3. Phenyl Bis-Sulfonamide Keap1-Nrf2 Protein-Protein Interaction Inhibitors with an Alternative Binding Mode

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

  • J Med Chem. 2022 May 26;65(10):7380-7398. doi: 10.1021/acs.jmedchem.2c00457.
Nikolaos Georgakopoulos 1 2,  Sandeep Talapatra 1,  Dina Dikovskaya 3,  Sharadha Dayalan Naidu 3,  Maureen Higgins 3,  Jemma Gatliff 1 2,  Aysel Ayhan 1,  Roxani Nikoloudaki 1 2,  Marjolein Schaap 1,  Klara Valko 1 4,  Farideh Javid 5,  Albena T Dinkova-Kostova 3 6,  Frank Kozielski 1,  Geoffrey Wells 1
Affiliations

Affiliations

  • 1 UCL School of Pharmacy, University College London, 29/39 Brunswick Square, London WC1N 1AX, U.K.
  • 2 Stevenage Bioscience Catalyst, Keregen Therapeutics Ltd., Gunnels Wood Rd, Stevenage SG1 2FX, U.K.
  • 3 Jacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, Scotland, U.K.
  • 4 Bio-Mimetic Chromatography Consultancy, 17 Cabot Close, Stevenage SG2 0ES, U.K.
  • 5 Department of Pharmacy, University of Huddersfield, Queensgate, Huddersfield HD1 3DH, U.K.
  • 6 Department of Pharmacology and Molecular Sciences and Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, United States.
PMID: 35549469 DOI: 10.1021/acs.jmedchem.2c00457
Abstract

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.

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