Discovery of GSK2795039, a Novel Small Molecule NADPH Oxidase 2 Inhibitor
Open accessAbstract
Aims: The NADPH oxidase (NOX) family of enzymes catalyzes the formation of reactive oxygen species (ROS). NOX enzymes not only have a key role in a variety of physiological processes but also contribute to oxidative stress in certain disease states. To date, while numerous small molecule inhibitors have been reported (in particular for NOX2), none have demonstrated inhibitory activity in vivo . As such, there is a need for the identification of improved NOX inhibitors to enable further evaluation of the biological functions of NOX enzymes in vivo as well as the therapeutic potential of NOX inhibition. In this study, both the in vitro and in vivo pharmacological profiles of GSK2795039, a novel NOX2 inhibitor, were characterized in comparison with other published NOX inhibitors. Results: GSK2795039 inhibited both the formation of ROS and the utilization of the enzyme substrates, NADPH and oxygen, in a variety of semirecombinant cell-free and cell-based NOX2 assays. It inhibited NOX2 in an NADPH competitive manner and was selective over other NOX isoforms, xanthine oxidase, and endothelial nitric oxide synthase enzymes. Following systemic administration in mice, GSK2795039 abolished the production of ROS by activated NOX2 enzyme in a paw inflammation model. Furthermore, GSK2795039 showed activity in a murine model of acute pancreatitis, reducing the levels of serum amylase triggered by systemic injection of cerulein. Innovation and Conclusions: GSK2795039 is a novel NOX2 inhibitor that is the first small molecule to demonstrate inhibition of the NOX2 enzyme in vivo . Antioxid. Redox Signal. 23, 358–374.
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Existing evidence suggests that GSK2795039 inhibits NOX2 through competition with NADPH for the binding site of the NOX2 dehydrogenase domain.
“Existing evidence suggests that GSK2795039 inhibits NOX2 through competition with NADPH for the binding site of the NOX2 dehydrogenase domain (435).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [435]
GSK2795039 appears to be specific toward NOX2 and does not show off-target effects toward eNOS or XO.
“GSK2795039 (FIGURE 10) appears to be specific toward NOX2 and does not show off-target effects toward eNOS or XO.”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [435]
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- Authors
- Hirano, K., Chen, W. S., Chueng, A. L. W., Dunne, A. A., Seredenina, T., Filippova, A., Ramachandran, S., Bridges, A., Chaudry, L., Pettman, G., Allan, C., Duncan, S., Lee, K. C., Lim, J., Ma, M. T., Ong, A. B., Ye, N. Y., Nasir, S., Mulyanidewi, S., Aw, C. C., Oon, P. P., Liao, S., Li, D., Johns, D. G., Miller, N. D., Davies, C. H., Browne, E. R., Matsuoka, Y., Chen, D. W., Jaquet, V., & Rutter, A. R.
- Affiliations
- GlaxoSmithKline (United Kingdom) (GB)
- University of Geneva (CH)
- University of Geneva
- Corresponding author
- Rutter, A. Richard
- Venue
- Antioxidants & Redox Signaling
- Publisher
- SAGE Publications
- Published
- 2015-08
- Volume
- 23
- Issue
- 5
- Pages
- 358-374
- ISSN
- 1523-0864 (ISSN-L)
- 1557-7716
- PMC
- PMC4545375
- OpenAlex
- W2402240200
- Cited by
- 205
- References
- 69
- Citations by year
- 2026: 19 · 2025: 23 · 2024: 27 · 2023: 30 · 2022: 17 · 2021: 22 · 2020: 24 · 2019: 20 · 2018: 7 · 2017: 5 · 2016: 7 · 2015: 3 · 2014: 1
- FWCI
- 3.62
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Antioxidants and Redox Signaling (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- GlaxoSmithKline
- European Commission (278611)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- NADPH oxidase 2, small molecule inhibitors, reactive oxygen species, oxidative stress, paw inflammation, acute pancreatitis, cerulein-induced pancreatitis, serum amylase, enzyme selectivity, xanthine oxidase, endothelial nitric oxide synthase, in vivo pharmacology
- MeSH terms
- NADPH Oxidase 2, Aminopyridines, Animals, Cells, Cultured, Enzyme Inhibitors, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Pancreatitis, Sulfonamides, Rats, Sprague-Dawley, Reactive Oxygen Species, NADPH Oxidases, Drug Discovery
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