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
  • 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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