title: Mechanism-based inhibition of quinone reductase 2 (NQO2): selectivity for NQO2 over NQO1 and structural basis for flavoprotein inhibition.
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.
authors.affiliation: School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, U.K.
authors.forename: Marine
authors.initials: M
authors.lastname: Dufour
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, 12700 East 19th Avenue, Aurora, Colorado 80045, U.S.A.
authors.forename: Chao
authors.initials: C
authors.lastname: Yan
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, 12700 East 19th Avenue, Aurora, Colorado 80045, U.S.A.
authors.forename: David
authors.initials: D
authors.lastname: Siegel
authors.affiliation: School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, U.K.
authors.forename: Marie A
authors.initials: MA
authors.lastname: Colucci
authors.affiliation: School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, U.K.
authors.forename: Matthew
authors.initials: M
authors.lastname: Jenner
authors.affiliation: School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, U.K.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Oldham
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, 12700 East 19th Avenue, Aurora, Colorado 80045, U.S.A.
authors.forename: Joe
authors.initials: J
authors.lastname: Gomez
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, 12700 East 19th Avenue, Aurora, Colorado 80045, U.S.A.
authors.forename: Philip
authors.initials: P
authors.lastname: Reigan
authors.affiliation: School of Pharmacy, Centre for Biomolecular Science, University of Nottingham, University Park, Nottingham NG7 2RD, U.K.
authors.forename: Yazhuo
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Pharmacy, Centre for Biomolecular Science, University of Nottingham, University Park, Nottingham NG7 2RD, U.K.
authors.forename: Cristina I
authors.initials: CI
authors.lastname: De Matteis
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, 12700 East 19th Avenue, Aurora, Colorado 80045, U.S.A.
authors.forename: David
authors.initials: D
authors.lastname: Ross
authors.affiliation: School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, U.K.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Moody
mesh_terms: D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005420:Flavoproteins / Q000037:antagonists & inhibitors*; D006801:Humans; D045563:Indolequinones / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors* / Q000235:genetics; D011808:Quinone Reductases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D005420:Flavoproteins; D045563:Indolequinones; D011994:Recombinant Proteins; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases