Development of an improved and specific inhibitor of NADPH oxidase 2 to treat traumatic brain injury

Mason, Hannah D.; Rai, Ganesha; Kozyr, A. V.; Jonge, Nathaniel De; Gliniewicz, Emily F.; Berg, Lars J; Wald, Gal; Dorrier, Cayce; Henderson, Mark J.; Zakharov, Alexey; Dyson, Tristan; Audley, John; Pettinato, Anthony M.; Padilha, Elias Carvalho; Shah, Pranav; Xu, Xin; Leto, Thomas L.; Simeonov, Anton; Zarember, Kol A.; McGavern, Dorian B.; Gallin, John I.

doi:10.1016/j.redox.2023.102611

Cited by 9 publications

(8 citation statements)

References 45 publications

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“…In primary mouse neutrophils, the compound was found less potent than 27 (IC 50 of 4.8 and 2.17 μM, respectively), suggesting that it might be less active in mouse. Finally, transcranial administration of 28 resulted in a good reduction of cortical cell death in a murine mild TBI model, with no beneficial effects in NOX2 knockout mice …”

Section: Nox Inhibitorsmentioning

confidence: 94%

“…The information obtained guided further structural optimization to improve the pharmacokinetic characteristics. Specifically, a group of different analogues of 27 was designed and synthesized, and their inhibitory activity against NOX2 was evaluated . Compound 28 (NCATS-SM7270) emerged as the best candidate, showing a 2-fold higher potency against NOX2 than parent compound 27 (IC 50 of 2.1 and 3.94 μM, respectively, in PMNs extracted from mouse granulocytes).…”

Section: Nox Inhibitorsmentioning

confidence: 99%

“…Finally, transcranial administration of 28 resulted in a good reduction of cortical cell death in a murine mild TBI model, with no beneficial effects in NOX2 knockout mice. 243 In 2019, Genkyotex developed compound 29 (GKT771, structure not disclosed) as a selective NOX1 inhibitor (K i of 60 nM) with a high degree of selectivity toward NOX4 (K i of 4 nM) and no activity against all other NOX isoforms, as well as xanthine oxidase and glucose oxidase and no scavenging properties. The activity of the compound was investigated both in a colon carcinoma and a melanoma mouse model.…”

Section: ■ Nox Inhibitorsmentioning

confidence: 99%

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NADPH Oxidases: From Molecular Mechanisms to Current Inhibitors

Cipriano,

Viviano,

Feoli

et al. 2023

J. Med. Chem.

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NADPH oxidases (NOXs) form a family of electrontransporting membrane enzymes whose main function is reactive oxygen species (ROS) generation. Strong evidence suggests that ROS produced by NOX enzymes are major contributors to oxidative damage under pathologic conditions. Therefore, blocking the undesirable actions of these enzymes is a therapeutic strategy for treating various pathological disorders, such as cardiovascular diseases, inflammation, and cancer. To date, identification of selective NOX inhibitors is quite challenging, precluding a pharmacologic demonstration of NOX as therapeutic targets in vivo. The aim of this Perspective is to furnish an updated outlook about the small-molecule NOX inhibitors described over the last two decades. Structures, activities, and in vitro/in vivo specificity are discussed, as well as the main biological assays used. ■ SIGNIFICANCE• ROS produced by NOXs are major contributors to oxidative damage in pathologic conditions. • Therefore, blocking the undesirable actions of these enzymes is a therapeutic strategy for treating various pathological disorders. • The aim of this Perspective is to provide insight on NOX proteins as targets and an overview and update on the current status of NOX inhibitors, including challenges and potential strategic directions for future progress in the field.

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Section: Nox Inhibitorsmentioning

confidence: 94%

Section: Nox Inhibitorsmentioning

confidence: 99%

Section: ■ Nox Inhibitorsmentioning

confidence: 99%

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NADPH Oxidases: From Molecular Mechanisms to Current Inhibitors

Cipriano,

Viviano,

Feoli

et al. 2023

J. Med. Chem.

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“…One potential strategy is to repurpose existing drugs used in neurological disorders, and several phenothiazine-based antipsychotic drugs have been shown to exhibit Nox2 inhibitory activity in vitro [ 25 , 27 ] and in vivo [ 28 ]. A separate approach based on medicinal chemistry-based modification of a Nox2 inhibitor of limited specificity, GSK2795039 [ 29 ], recently resulted in the development of a more specific Nox2 inhibitor, NCATS-SM7270, which shows protective effects against traumatic brain injury [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Novel NADPH Oxidase-2 Inhibitors as Potential Anti-Inflammatory and Neuroprotective Agents

Juric,

Rawat,

Amaradhi

et al. 2023

Antioxidants

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A family of seven NADPH oxidase enzymes (Nox1-5, Duox1-2) has been implicated in a variety of diseases, including inflammatory lung diseases, neurodegenerative diseases, cardiovascular diseases, and cancer. Here, we report the results of our studies aimed at developing novel brain-permeable Nox2 inhibitors with potential application as neuroprotective agents. Using cell-based assays, we identified a novel Nox2 inhibitor, TG15-132, that prevents PMA-stimulated oxygen consumption and reactive oxygen species (superoxide radical anion and hydrogen peroxide) formation upon acute treatment in differentiated HL60 cells. Long-term treatment with TG15-132 attenuates the induction of genes encoding Nox2 subunits, several inflammatory cytokines, and iNOS in differentiated THP-1 cells. Moreover, TG15-132 shows a relatively long plasma half-life (5.6 h) and excellent brain permeability, with a brain-to-plasma ratio (>5-fold) in rodent models. Additionally, TG15-132 does not cause any toxic effects on vital organs or blood biomarkers of toxicity in mice upon chronic dosing for seven days. We propose that TG15-132 may be used as a Nox2 inhibitor and a potential neuroprotective agent, with possible further structural modifications to increase its potency.

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“…Several NOX2 inhibitors including both peptides and small molecules have been reported. − However, most of these have issues with off-target binding, isoform selectivity, oxidative effects, chemical liabilities, or assay-interference properties, with GSK2795039 and its analogue NCATS-SM7270 as potential exceptions to this. , Small-molecule p47phox–p22phox inhibitors have also been reported, for example LMH001, CPP11G, C6, and ebselen . However, ebselen is nonspecific in its action and even shown to induce aggregation of p47phox via a covalent mechanism, and LMH001 is chemically very unstable. , CPP11G (or CPP11H) and C6 have not been shown to directly bind p47phox using biophysical experiments, but this has been demonstrated for two other small-molecule series: Garsi et al recently reported some peptide-derived triproline mimetics developed by structure-based drug discovery, which showed binding to p47phox by surface plasmon resonance (SPR) .…”

Section: Introductionmentioning

confidence: 99%

Targeting NOX2 with Bivalent Small-Molecule p47phox–p22phox Inhibitors

Zang,

Peters,

Cambet

et al. 2023

J. Med. Chem.

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Nicotinamide adenine dinucleotide phosphate oxidase isoform 2 (NOX2) is an enzymatic complex whose function is the regulated generation of reactive oxygen species (ROS). NOX2 activity is central to redox signaling events and antibacterial response, but excessive ROS production by NOX2 leads to oxidative stress and inflammation in a range of diseases. The protein− protein interaction between the NOX2 subunits p47phox and p22phox is essential for NOX2 activation, thus p47phox is a potential drug target. Previously, we identified 2-aminoquinoline as a fragment hit toward p47phox SH3A-B and converted it to a bivalent smallmolecule p47phox−p22phox inhibitor (K i = 20 μM). Here, we systematically optimized the bivalent compounds by exploring linker types and positioning as well as substituents on the 2-aminoquinoline part and characterized the bivalent binding mode with biophysical methods. We identified several compounds with submicromolar binding affinities and cellular activity and thereby demonstrated that p47phox can be targeted by potent small molecules.

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Development of an improved and specific inhibitor of NADPH oxidase 2 to treat traumatic brain injury

Cited by 9 publications

References 45 publications

NADPH Oxidases: From Molecular Mechanisms to Current Inhibitors

NADPH Oxidases: From Molecular Mechanisms to Current Inhibitors

Novel NADPH Oxidase-2 Inhibitors as Potential Anti-Inflammatory and Neuroprotective Agents

Targeting NOX2 with Bivalent Small-Molecule p47phox–p22phox Inhibitors

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