These authors contributed equally to this work.
Mechanism-Based Inhibition of Quinone Reductase 2 (NQO2): Selectivity for NQO2 over NQO1 and Structural Basis for Flavoprotein Inhibition
Article first published online: 19 APR 2011
Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Volume 12, Issue 8, pages 1203–1208, May 16, 2011
How to Cite
Dufour, M., Yan, C., Siegel, D., Colucci, M. A., Jenner, M., Oldham, N. J., Gomez, J., Reigan, P., Li, Y., De Matteis, C. I., Ross, D. and Moody, C. J. (2011), Mechanism-Based Inhibition of Quinone Reductase 2 (NQO2): Selectivity for NQO2 over NQO1 and Structural Basis for Flavoprotein Inhibition. ChemBioChem, 12: 1203–1208. doi: 10.1002/cbic.201100085
- Issue published online: 16 MAY 2011
- Article first published online: 19 APR 2011
- Manuscript Received: 3 FEB 2011
- National Cancer Institute. Grant Number: R01-CA114441
- protein structure;
- redox chemistry
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.