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Mechanism-Based Inhibition of Quinone Reductase 2 (NQO2): Selectivity for NQO2 over NQO1 and Structural Basis for Flavoprotein Inhibition

Authors

  • Marine Dufour,

    1. School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD (UK), Fax: (+44) 115-951-3564
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    • These authors contributed equally to this work.

  • Chao Yan,

    1. Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, 12700 East 19th Avenue, Aurora, Colorado 80045 (USA), Fax: (+1) 303-724-7266
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    • These authors contributed equally to this work.

  • Dr. David Siegel,

    1. Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, 12700 East 19th Avenue, Aurora, Colorado 80045 (USA), Fax: (+1) 303-724-7266
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  • Dr. Marie A. Colucci,

    1. School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD (UK), Fax: (+44) 115-951-3564
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  • Matthew Jenner,

    1. School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD (UK), Fax: (+44) 115-951-3564
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  • Dr. Neil J. Oldham,

    1. School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD (UK), Fax: (+44) 115-951-3564
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  • Joe Gomez,

    1. Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, 12700 East 19th Avenue, Aurora, Colorado 80045 (USA), Fax: (+1) 303-724-7266
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  • Dr. Philip Reigan,

    1. Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, 12700 East 19th Avenue, Aurora, Colorado 80045 (USA), Fax: (+1) 303-724-7266
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  • Yazhuo Li,

    1. School of Pharmacy, Centre for Biomolecular Science, University of Nottingham, University Park, Nottingham NG7 2RD (UK)
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  • Dr. Cristina I. De Matteis,

    1. School of Pharmacy, Centre for Biomolecular Science, University of Nottingham, University Park, Nottingham NG7 2RD (UK)
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  • Prof. Dr. David Ross,

    Corresponding author
    1. Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, 12700 East 19th Avenue, Aurora, Colorado 80045 (USA), Fax: (+1) 303-724-7266
    • Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, 12700 East 19th Avenue, Aurora, Colorado 80045 (USA), Fax: (+1) 303-724-7266
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  • Prof. Dr. Christopher J. Moody

    Corresponding author
    1. School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD (UK), Fax: (+44) 115-951-3564
    • School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD (UK), Fax: (+44) 115-951-3564
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Abstract

A role for the flavoprotein NRH:quinone oxidoreductase 2 (NQO2, QR2) in human diseases such as malaria, leukemia and neurodegeneration has been proposed. In order to explore the potential of NQO2 as a therapeutic target, we have developed potent and selective mechanism-based inhibitors centered on the indolequinone pharmacophore. The compounds show remarkable selectivity for NQO2 over the closely related flavoprotein NQO1, with small structural changes defining selectivity. Biochemical studies confirmed the mechanism-based inhibition, whereas X-ray crystallography and mass spectrometry revealed the nature of the inhibitor interaction with the protein. These indolequinones represent the first mechanism-based inhibitors of NQO2, and their novel mode of action involving alkylation of the flavin cofactor, provides significant advantages over existing competitive inhibitors in terms of potency and irreversibility, and will open new opportunities to define the role of NQO2 in disease.

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