2. Academic Validation
  3. Enhancing Selectivity and Potency of SNAr Covalent Inhibitors of NADPH Oxidase Enzymes

Enhancing Selectivity and Potency of SNAr Covalent Inhibitors of NADPH Oxidase Enzymes

  • J Med Chem. 2025 Jul 10;68(13):14072-14084. doi: 10.1021/acs.jmedchem.5c01272.
Blessing C Ogboo 1,  Kishan B Patel 1,  Marta Massari 2,  Sara Marchese 2,  Joana Reis 2,  Emily J Joyce 3,  Miao-Chong J Lin 3,  Johnathan D Rabb 1,  Omobolanle A Abidakun 1,  Qing Lin 1,  Albert van der Vliet 3,  Andrea Mattevi 2,  David E Heppner 1 4 5 6
Affiliations

Affiliations

  • 1 Department of Chemistry, College of Arts and Sciences, The State University of New York at Buffalo, Buffalo, New York 14260, United States.
  • 2 Department of Biology and Biotechnology, University of Pavia, Pavia 27100, Italy.
  • 3 Department of Pathology and Laboratory Medicine, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, Vermont 05405, United States.
  • 4 Department of Structural Biology, Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York 14203, United States.
  • 5 Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14214, United States.
  • 6 Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14203, United States.
PMID: 40537977 DOI: 10.1021/acs.jmedchem.5c01272
Abstract

Dysregulated Reactive Oxygen Species (ROS) are implicated in various diseases, positioning NADPH Oxidase enzymes (NOXs) as attractive therapeutic targets. However, progress in tool compound discovery has been hindered by rational optimization strategies that can improve isoform selectivity. Starting from a nonselective but well-behaved NOX inhibitor (VAS2870), we have discovered a first-in-class NOX5 selective inhibitor through minor functionalization on a benzoxazolethiol moiety, which is released upon covalent modification to the target enzyme. These unexpected findings showcase a unique strategy for optimizing SNAr covalent inhibitors and offer new avenues for the development of isoform-selective NOX inhibitors.

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