title: Evolution of NADPH Oxidase Inhibitors: Selectivity and Mechanisms for Target Engagement.
abstract: CONCLUSIONS
  Oxidative stress, an excess of reactive oxygen species (ROS) production versus consumption, may be involved in the pathogenesis of different diseases. The only known enzymes solely dedicated to ROS generation are nicotinamide adenine dinucleotide phosphate (NADPH) oxidases with their catalytic subunits (NOX). After the clinical failure of most antioxidant trials, NOX inhibitors are the most promising therapeutic option for diseases associated with oxidative stress.
  
  
  BACKGROUND
  Historical NADPH oxidase inhibitors, apocynin and diphenylene iodonium, are un-specific and not isoform selective. Novel NOX inhibitors stemming from rational drug discovery approaches, for example, GKT137831, ML171, and VAS2870, show improved specificity for NADPH oxidases and moderate NOX isoform selectivity. Along with NOX2 docking sequence (NOX2ds)-tat, a peptide-based inhibitor, the use of these novel small molecules in animal models has provided preliminary in vivo evidence for a pathophysiological role of specific NOX isoforms.
  
  
  RESULTS
  Here, we discuss whether novel NOX inhibitors enable reliable validation of NOX isoforms' pathological roles and whether this knowledge supports translation into pharmacological applications. Modern NOX inhibitors have increased the evidence for pathophysiological roles of NADPH oxidases. However, in comparison to knockout mouse models, NOX inhibitors have limited isoform selectivity. Thus, their use does not enable clear statements on the involvement of individual NOX isoforms in a given disease.
  
  
  CONCLUSIONS
  The development of isoform-selective NOX inhibitors and biologicals will enable reliable validation of specific NOX isoforms in disease models other than the mouse. Finally, GKT137831, the first NOX inhibitor in clinical development, is poised to provide proof of principle for the clinical potential of NOX inhibition.
authors.affiliation: Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University , Maastricht, the Netherlands .
authors.forename: Sebastian
authors.initials: S
authors.lastname: Altenhöfer
authors.affiliation: Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University , Maastricht, the Netherlands .
authors.forename: Kim A
authors.initials: KA
authors.lastname: Radermacher
authors.affiliation: Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University , Maastricht, the Netherlands .
authors.forename: Pamela W M
authors.initials: PW
authors.lastname: Kleikers
authors.affiliation: Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University , Maastricht, the Netherlands .
authors.forename: Kirstin
authors.initials: K
authors.lastname: Wingler
authors.affiliation: Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University , Maastricht, the Netherlands .
authors.forename: Harald H H W
authors.initials: HH
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D019143:Evolution, Molecular; D006801:Humans; D008024:Ligands; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D020033:Protein Isoforms; D019255:NADPH Oxidases