2. Academic Validation
  3. Targeting NOX2 with Bivalent Small-Molecule p47phox-p22phox Inhibitors

Targeting NOX2 with Bivalent Small-Molecule p47phox-p22phox Inhibitors

  • J Med Chem. 2023 Oct 19. doi: 10.1021/acs.jmedchem.3c01548.
Jie Zang 1,  Felix Peters 1,  Yves Cambet 2,  Eugenia Cifuentes-Pagano 3 4,  Munira Mohamed Shishay Hissabu 1,  Christopher M Dustin 3 4,  Lars Henrik Svensson 1,  Martin Mariboe Olesen 1,  Mathias Feldt Lomholt Poulsen 1,  Stig Jacobsen 1,  Pernille Sønderby Tuelung 1,  Dilip Narayanan 1,  Annette Eva Langkilde 1,  Michael Gajhede 1,  Patrick J Pagano 3 4,  Vincent Jaquet 2 5,  Frederik Vilhardt 6,  Anders Bach 1
Affiliations

Affiliations

  • 1 Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
  • 2 READS unit, Centre Médical Universitaire, University of Geneva, Geneva CH-1211, Switzerland.
  • 3 Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.
  • 4 Department of Pharmacology and ChemicalBiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.
  • 5 Department of Pathology and Immunology, Centre Médical Universitaire, University of Geneva, Geneva CH-1211, Switzerland.
  • 6 Institute of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
PMID: 37857466 DOI: 10.1021/acs.jmedchem.3c01548
Abstract

Nicotinamide adenine dinucleotide phosphate oxidase isoform 2 (NOX2) is an enzymatic complex whose function is the regulated generation of Reactive Oxygen Species (ROS). NOX2 activity is central to redox signaling events and Antibacterial response, but excessive ROS production by NOX2 leads to oxidative stress and inflammation in a range of diseases. The protein-protein interaction between the NOX2 subunits p47phox and p22phox is essential for NOX2 activation, thus p47phox is a potential drug target. Previously, we identified 2-aminoquinoline as a fragment hit toward p47phoxSH3A-B and converted it to a bivalent small-molecule p47phox-p22phox inhibitor (Ki = 20 μM). Here, we systematically optimized the bivalent compounds by exploring linker types and positioning as well as substituents on the 2-aminoquinoline part and characterized the bivalent binding mode with biophysical methods. We identified several compounds with submicromolar binding affinities and cellular activity and thereby demonstrated that p47phox can be targeted by potent small molecules.

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