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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)
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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)

Articles citing this publication (8)

  1. Design and characterization of a heterobifunctional degrader of KEAP1. Chen H, Nguyen NH, Magtoto CM, Cobbold SA, Bidgood GM, Meza Guzman LG, Richardson LW, Corbin J, Au AE, Lechtenberg BC, Feltham R, Sutherland KD, Grohmann C, Nicholson SE, Sleebs BE. Redox Biol 59 102552 (2023)
  2. Importance of Binding Site Hydration and Flexibility Revealed When Optimizing a Macrocyclic Inhibitor of the Keap1-Nrf2 Protein-Protein Interaction. Begnini F, Geschwindner S, Johansson P, Wissler L, Lewis RJ, Lewis RJ, Danelius E, Luttens A, Matricon P, Carlsson J, Lenders S, König B, Friedel A, Sjö P, Schiesser S, Kihlberg J. J Med Chem 65 3473-3517 (2022)
  3. Turning Nonselective Inhibitors of Type I Protein Arginine Methyltransferases into Potent and Selective Inhibitors of Protein Arginine Methyltransferase 4 through a Deconstruction-Reconstruction and Fragment-Growing Approach. Iannelli G, Milite C, Marechal N, Cura V, Bonnefond L, Troffer-Charlier N, Feoli A, Rescigno D, Wang Y, Cipriano A, Viviano M, Bedford MT, Cavarelli J, Castellano S, Sbardella G. J Med Chem 65 11574-11606 (2022)
  4. A potent phosphodiester Keap1-Nrf2 protein-protein interaction inhibitor as the efficient treatment of Alzheimer's disease. Sun Y, Xu L, Zheng D, Wang J, Liu G, Mo Z, Liu C, Zhang W, Yu J, Xing C, He L, Zhuang C. Redox Biol 64 102793 (2023)
  5. Efficient Hit-to-Lead Searching of Kinase Inhibitor Chemical Space via Computational Fragment Merging. Andrianov GV, Gabriel Ong WJ, Serebriiskii I, Karanicolas J. J Chem Inf Model 61 5967-5987 (2021)
  6. Use of Deep-Learning Assisted Assessment of Cardiac Parameters in Zebrafish to Discover Cyanidin Chloride as a Novel Keap1 Inhibitor Against Doxorubicin-Induced Cardiotoxicity. Liu C, Wang Y, Zeng Y, Kang Z, Zhao H, Qi K, Wu H, Zhao L, Wang Y. Adv Sci (Weinh) 10 e2301136 (2023)
  7. In Vitro and In Vivo Evaluation of Pellotine: A Hypnotic Lophophora Alkaloid. Poulie CBM, Chan CB, Parka A, Lettorp M, Vos J, Raaschou A, Pottie E, Bundgaard MS, Sørensen LME, Cecchi CR, Märcher-Rørsted E, Bach A, Herth MM, Decker A, Jensen AA, Elfving B, Kretschmann AC, Stove CP, Kohlmeier KA, Cornett C, Janfelt C, Kornum BR, Kristensen JL. ACS Pharmacol Transl Sci 6 1492-1507 (2023)
  8. A Multifunctional (-)-Meptazinol-Serotonin Hybrid Ameliorates Oxidative Stress-Associated Apoptotic Neuronal Death and Memory Deficits via Activating the Nrf2/Antioxidant Enzyme Pathway. Zhao F, Zhao L, Zhou Y, Tan X, Yang Y, Ni W, Zheng W, Chen H, Qiu Y, Li J. Oxid Med Cell Longev 2023 6935947 (2023)


Related citations provided by authors (1)

  1. Towards automated crystallographic structure refinement with phenix.refine.. Afonine PV, Grosse-Kunstleve RW, Echols N, Headd JJ, Moriarty NW, Mustyakimov M, Terwilliger TC, Urzhumtsev A, Zwart PH, Adams PD Acta Crystallogr. D Biol. Crystallogr. 68 352-367 (2012)

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