NADPH oxidase (NOX) enzymes are major sources of reactive oxygen species (ROS). In particular, NOX mediates signaling events in a variety of physiological processes, such as hormone biosynthesis, cell signaling, and microbial killing. Especially, NOX enzymes not only have a key role in a variety of physiological processes but also contribute to oxidative stress in certain disease states. The gp91phox/NOX2 subunit is the electron transfer chain of the active NADPH oxidase because it has binding sites for FAD, NADPH and two hemes. GSK2795039 is a potent inhibitor of NADPH oxidase 2 (NOX2) in cell-free and whole-cell assays. GSK2795039 inhibits NOX2 in an NADPH competitive manner and is selective over other NOX isoforms, xanthine oxidase, and endothelial nitric oxide synthase enzymes.

In this study, Kazufumi Hirano, et al characterized the pharmacological profiles of GSK2795039 in comparison with other NOX inhibitors. GSK2795039 directly inhibits NADPH oxidase 2 NOX2. In the semirecombinant system, GSK2795039 is a potent inhibitor of NOX2-dependent ROS production and NADPH utilization. The addition of the NOX2 inhibitor GSK2795039 significantly reduces the presence of caspase-3-positive PC12 cells. Moreover, GSK2795039 inhibits both the formation of ROS and the utilization of the enzyme substrates, NADPH and oxygen.

Following systemic administration in mice, GSK2795039 abolishes the production of ROS by activating NOX2 enzyme in a paw inflammation model. Furthermore, GSK2795039 shows activity in a murine model of acute pancreatitis, reducing the levels of serum amylase triggered by systemic injection of cerulein. GSK2795039 shows in vivo target engagement in the periphery as well as protective effects in a model of acute pancreatitis.

Hirano K, et al. Discovery of GSK2795039, a Novel Small Molecule NADPH Oxidase 2 Inhibitor. Antioxid Redox Signal. 2015 Aug 10;23(5):358-74.