GSK2795039
目录号 : GC32681
A NOX2 inhibitor
Cas No.:1415925-18-6
Sample solution is provided at 25 µL, 10mM.
Quality Control & SDS
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- Purity: >99.50%
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GSK2795039 is an inhibitor of NADPH oxidase 2 (NOX2; IC50 = 0.269 ?M).1 It is selective for NOX2 over NOX1, -3, -4, and -5 (IC50s = >1,000 ?M for all), as well as xanthine oxidase and PKCβ (IC50s = 28.8 and 10 ?M, respectively). GSK2795039 inhibits NOX2-mediated production of reactive oxygen species (ROS) and NADPH depletion in cell-free assays (IC50s = 0.537 and 0.251 ?M, respectively). In vivo, GSK2795039 (100 mg/kg) reduces serum levels of amylase, a marker for pancreatic cell necrosis, in a gp91phox knockout mouse model of acute pancreatitis. GSK2795039 also inhibits brain NOX2 activity, decreases neurite shortening and apoptosis, and attenuates neurological deficits in a mouse model of weight drop-induced traumatic brain injury (TBI).2
1.Hirano, K., Chen, W.S., Chueng, A.L.W., et al.Discovery of GSK2795039, a novel small molecule NADPH oxidase 2 inhibitorAntioxid. Redox Signal.23(5)(2015) 2.Wang, M., and Luo, L.An effective NADPH oxidase 2 inhibitor provides neuroprotection and improves functional outcomes in animal model of traumatic brain injuryNeurochem. Res.45(5)1097-1106(2020)
| Cas No. | 1415925-18-6 | SDF | |
| Canonical SMILES | CC(C)N1C=C(C2=CC=C(CCN3C)C3=C2)C4=C1N=CC=C4NS(C5=NN(C)C=C5)(=O)=O | ||
| 分子式 | C23H26N6O2S | 分子量 | 450.56 |
| 溶解度 | DMSO : ≥ 32 mg/mL (71.02 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.2195 mL | 11.0973 mL | 22.1946 mL |
| 5 mM | 0.4439 mL | 2.2195 mL | 4.4389 mL |
| 10 mM | 0.2219 mL | 1.1097 mL | 2.2195 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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2.
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NOX2 inhibitor GSK2795039 metabolite identification towards drug optimization
J Pharm Biomed Anal 2021 Jul 15;201:114102.PMID:33992989DOI:10.1016/j.jpba.2021.114102.
Overproduction of reactive oxygen species (ROS) can lead to several disease states, such as diabetic nephropathy and amyotrophic lateral sclerosis. One of the most studied mechanisms to inhibit the over production of ROS is the inhibition of NADPH oxidase (NOX) enzymes, which catalyze the conversion of cytoplasmic NADPH to NADP+, resulting in the formation of superoxide anions. GSK2795039 has been shown to selectively inhibit the NOX2 isoform, however, clearance of the compound was high in rats and mice. Therefore, identifying metabolic soft spots would be crucial in guiding the optimization process to improve its pharmacokinetic properties. GSK2795039 (10 μM) was incubated in the presence of mouse, rat and human liver microsomal (1 mg/mL) and cytosolic (2 mg/mL) fractions and appropriate co-factors, followed by MSe fragment analysis to identify metabolic soft spots. GSK2795039 showed marked species differences in its metabolism. The alkyl side chains and indoline moiety were the most common sites of biotransformation. The compound was identified to be an aldehyde oxidase substrate. Additionally, unique human metabolites were observed in vitro. Our study sheds light on structure optimization opportunities for developing improved NOX2 inhibitors, and it will help overcome the challenges involved in preclinical species selection for its safety evaluations.
The NADPH Oxidase Family and Its Inhibitors
Antioxid Redox Signal 2020 Aug 10;33(5):332-353.PMID:31826639DOI:10.1089/ars.2019.7915.
Significance: The oxidative stress, resulting from an imbalance in the production and scavenging of reactive oxygen species (ROS), is known to be involved in the development and progression of several pathologies. The excess of ROS production is often due to an overactivation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) and for this reason these enzymes became promising therapeutic targets. However, even if NOX are now well characterized, the development of new therapies is limited by the lack of highly isoform-specific inhibitors. Recent Advances: In the past decade, several groups and laboratories have screened thousands of molecules to identify new specific inhibitors with low off-target effects. These works have led to the characterization of several new potent NOX inhibitors; however, their specificity varies a lot depending on the molecules. Critical Issues: Here, we are reviewing more than 25 known NOX inhibitors, focusing mainly on the newly identified ones such as APX-115, NOS31, Phox-I1 and 2, GLX7013114, and GSK2795039. To have a better overall view of these molecules, the inhibitors were classified according to their specificity, from pan-NOX inhibitors to highly isoform-specific ones. We are also presenting the use of these compounds both in vitro and in vivo. Future Directions: Several of these new molecules are potent and very specific inhibitors that could be good candidates for the development of new drugs. Even if the results are very promising, most of these compounds were only validated in vitro or in mice models and further investigations will be required before using them as potential therapies.
GSK2795039 prevents RIP1-RIP3-MLKL-mediated cardiomyocyte necroptosis in doxorubicin-induced heart failure through inhibition of NADPH oxidase-derived oxidative stress
Toxicol Appl Pharmacol 2023 Mar 15;463:116412.PMID:36764612DOI:10.1016/j.taap.2023.116412.
Doxorubicin (DOX), which is widely used for the treatment of cancer, induces cardiomyopathy associated with NADPH oxidase-derived reactive oxygen species. GSK2795039 is a novel small molecular NADPH oxidase 2 (Nox2) inhibitor. In this study, we investigated whether GSK2795039 prevents receptor-interacting protein kinase 1 (RIP1)-RIP3-mixed lineage kinase domain-like protein (MLKL)-mediated cardiomyocyte necroptosis in DOX-induced heart failure through NADPH oxidase inhibition. Eight-week old mice were randomly divided into 4 groups: control, GSK2795039, DOX and DOX plus GSK2795039. H9C2 cardiomyocytes were treated with DOX and GSK2795039. In DOX-treated mice, the survival rate was reduced, left ventricular (LV) end-systolic dimension was increased and LV fractional shortening was decreased, and these alterations were attenuated by the GSK2795039 treatment. GSK2795039 inhibited not only myocardial NADPH oxidase subunit gp91phox (Nox2) protein, but also p22phox, p47phox and p67phox proteins and prevented oxidative stress 8-hydroxy-2'-deoxyguanosine levels in DOX-treated mice. RIP3 protein and phosphorylated RIP1 (p-RIP1), p-RIP3 and p-MLKL proteins, reflective of their respective kinase activities, markers of necroptosis, were markedly increased in DOX-treated mice, and the increases were prevented by GSK2795039. GSK2795039 prevented the increases in serum lactate dehydrogenase and myocardial fibrosis in DOX-treated mice. Similarly, in DOX-treated cardiomyocytes, GSK2795039 improved cell viability, attenuated apoptosis and necrosis and prevented the increases in p-RIP1, p-RIP3 and p-MLKL expression. In conclusion, GSK2795039 prevents RIP1-RIP3-MLKL-mediated cardiomyocyte necroptosis through inhibition of NADPH oxidase-derived oxidative stress, leading to the improvement of myocardial remodeling and function in DOX-induced heart failure. These findings suggest that GSK2795039 may have implications for the treatment of DOX-induced cardiomyopathy.
Discovery of GSK2795039, a Novel Small Molecule NADPH Oxidase 2 Inhibitor
Antioxid Redox Signal 2015 Aug 10;23(5):358-74.PMID:26135714DOI:10.1089/ars.2014.6202.
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.
Selective Pharmacological Inhibition of NOX2 by GSK2795039 Improves Bladder Dysfunction in Cyclophosphamide-Induced Cystitis in Mice
Antioxidants (Basel) 2022 Dec 30;12(1):92.PMID:36670953DOI:10.3390/antiox12010092.
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic inflammatory disease without consistently effective treatment. Among the many mediators implicated in cystitis, the overproduction of reactive oxygen species (ROS) seems to play a key role, although the main source of ROS remains unclear. This study aimed to investigate the contribution of NADPH oxidase (NOX) isoforms in ROS generation and the voiding dysfunction of cyclophosphamide (CYP, 300 mg/Kg, ip, 24 h)-induced cystitis in adult female mice, a well-recognized animal model to study IC/BPS, by using GKT137831 (5 mg/Kg, ip, three times in a 24 h period) or GSK2795039 (5 mg/Kg, ip, three times in a 24 h period) to inhibit NOX1/4 or NOX2, respectively. Our results showed that treatment with GSK2795039 improved the dysfunctional voiding behavior induced by CYP, reduced bladder edema and inflammation, and preserved the urothelial barrier integrity and tight junction occludin expression, besides inhibiting the characteristic vesical pain and bladder superoxide anion generation. In contrast, the NOX1/4 inhibitor GKT137831 had no significant protective effects. Taken together, our in vivo and ex vivo data demonstrate that NOX2 is possibly the main source of ROS observed in cystitis-induced CYP in mice. Therefore, selective inhibition of NOX2 by GSK2795039 may be a promising target for future therapies for IC/BPS.