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Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds.

Pallesen JS, Narayanan D, Tran KT, Solbak SMØ, Marseglia G, Sørensen LME, Høj LJ, Munafò F, Carmona RMC, Garcia AD, Desu HL, Brambilla R, Johansen TN, Popowicz GM, Sattler M, Gajhede M, Bach A
J Med Chem 64 4623-4661 (2021)
Related entries: 6zew, 6zex, 6zey, 6zf0, 6zf1, 6zf2, 6zf3, 6zf4, 6zf5, 6zf6, 6zf7, 6zf8

Cited: 11 times
EuropePMC logo PMID: 33818106

Abstract

Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound

Reviews citing this publication (3)

  1. Targeting NRF2 to treat cancer. Sivinski J, Zhang DD, Chapman E. Semin Cancer Biol 76 61-73 (2021)
  2. KEAP1-NRF2 protein-protein interaction inhibitors: Design, pharmacological properties and therapeutic potential. Crisman E, Duarte P, Dauden E, Cuadrado A, Rodríguez-Franco MI, López MG, León R. Med Res Rev 43 237-287 (2023)
  3. E3 Ligases Meet Their Match: Fragment-Based Approaches to Discover New E3 Ligands and to Unravel E3 Biology. Michaelides IN, Collie GW. J Med Chem 66 3173-3194 (2023)

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