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NADPH oxidase 4

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Target id: 3004

Nomenclature: NADPH oxidase 4

Abbreviated Name: NOX4

Family: NADPH oxidases

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 578 11q14.3 NOX4 NADPH oxidase 4
Mouse 6 578 7 D3 Nox4 NADPH oxidase 4
Rat 6 578 1q32 Nox4 NADPH oxidase 4
Gene and Protein Information Comments
The human gene gives rise to multiple transcripts and protein isoforms (a-g). Variant 1/Isoform a is detailed in the table above. Three transcripts and protein isoforms have been identified from the mouse gene, and we include the longest isoform in the table above.
Previous and Unofficial Names Click here for help
KOX | KOX-1 | RENOX
Database Links Click here for help
Alphafold Q9NPH5 (Hs), Q9JHI8 (Mm), Q924V1 (Rn)
ChEMBL Target CHEMBL1250375 (Hs)
Ensembl Gene ENSG00000086991 (Hs), ENSMUSG00000030562 (Mm), ENSRNOG00000013925 (Rn)
Entrez Gene 50507 (Hs), 50490 (Mm), 85431 (Rn)
Human Protein Atlas ENSG00000086991 (Hs)
KEGG Gene hsa:50507 (Hs), mmu:50490 (Mm), rno:85431 (Rn)
OMIM 605261 (Hs)
Pharos Q9NPH5 (Hs)
RefSeq Nucleotide NM_016931 (Hs), NM_015760 (Mm), NM_053524 (Rn)
RefSeq Protein NP_058627 (Hs), NP_056575 (Mm), NP_445976 (Rn)
UniProtKB Q9NPH5 (Hs), Q9JHI8 (Mm), Q924V1 (Rn)
Wikipedia NOX4 (Hs)

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 87 [PMID: 20942471] Small molecule or natural product Primary target of this compound Hs Inhibition 7.3 pKi 7
⤷ pKi 7.3 (Ki 4.7x10-8 M) [7]
Description: Measured as inhibition of ROS production by hNOX4 in a cell free assay using membranes prepared from cells expressing hNOX4.
compound 7c [PMID: 22041175] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.1 pKi 3
⤷ pKi 7.1 (Ki 7.2x10-8 M) [3]
setanaxib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.0 pKi 1
⤷ pKi 7.0 (Ki 1.1x10-7 M) [1]
GKT136901 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 6.8 pKi 7
⤷ pKi 6.8 (Ki 1.65x10-7 M) [7]
Description: Cell free assay of ROS production by NOX4 membranes.
Inhibitor Comments
Three potential Nox4 inhibitors are reported by Xu et al. (2018), the most potent of which was compound 25 which exhibited an IC50 of 500 nM in a cell based assay [12]. These novel compounds have not been tested in a direct Nox4 activity assay, nor has selectivity been determined.
Immunopharmacology Comments
Nox4 is a known driver of the fibrotic process. We have included Nox4 in GToImmunoPdb based on the association between fibrosis and inflammation.
Immuno Process Associations
Immuno Process:  Inflammation
General Comments
Nox4 influences multiple normal biological processes by constitutively generating hydrogen peroxide (H2O2). It is also implicated in disease development, notably in conditions involving ischemia or fibrosis. Nox4 biosynthesis is reported to be upregulated in hypertension [8], cardiac hypertrophy [6], atherosclerosis [11], diabetic nephropathy [10], pulmonary hypertension [2], and pulmonary fibrosis [4-5,9]. Thus, small-molecule pharmacologic inhibitors of Nox4 offer therapeutic potential for this wide spectrum of diseases.

References

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1. Aoyama T, Paik YH, Watanabe S, Laleu B, Gaggini F, Fioraso-Cartier L, Molango S, Heitz F, Merlot C, Szyndralewiez C et al.. (2012) Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent. Hepatology, 56 (6): 2316-27. [PMID:22806357]

2. Barman SA, Chen F, Su Y, Dimitropoulou C, Wang Y, Catravas JD, Han W, Orfi L, Szantai-Kis C, Keri G et al.. (2014) NADPH oxidase 4 is expressed in pulmonary artery adventitia and contributes to hypertensive vascular remodeling. Arterioscler Thromb Vasc Biol, 34 (8): 1704-15. [PMID:24947524]

3. Gaggini F, Laleu B, Orchard M, Fioraso-Cartier L, Cagnon L, Houngninou-Molango S, Gradia A, Duboux G, Merlot C, Heitz F et al.. (2011) Design, synthesis and biological activity of original pyrazolo-pyrido-diazepine, -pyrazine and -oxazine dione derivatives as novel dual Nox4/Nox1 inhibitors. Bioorg Med Chem, 19 (23): 6989-99. [PMID:22041175]

4. Ghatak S, Hascall VC, Markwald RR, Feghali-Bostwick C, Artlett CM, Gooz M, Bogatkevich GS, Atanelishvili I, Silver RM, Wood J et al.. (2017) Transforming growth factor β1 (TGFβ1)-induced CD44V6-NOX4 signaling in pathogenesis of idiopathic pulmonary fibrosis. J Biol Chem, 292 (25): 10490-10519. [PMID:28389561]

5. Hecker L, Vittal R, Jones T, Jagirdar R, Luckhardt TR, Horowitz JC, Pennathur S, Martinez FJ, Thannickal VJ. (2009) NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nat Med, 15 (9): 1077-81. [PMID:19701206]

6. Kuroda J, Ago T, Matsushima S, Zhai P, Schneider MD, Sadoshima J. (2010) NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart. Proc Natl Acad Sci USA, 107 (35): 15565-70. [PMID:20713697]

7. Laleu B, Gaggini F, Orchard M, Fioraso-Cartier L, Cagnon L, Houngninou-Molango S, Gradia A, Duboux G, Merlot C, Heitz F et al.. (2010) First in class, potent, and orally bioavailable NADPH oxidase isoform 4 (Nox4) inhibitors for the treatment of idiopathic pulmonary fibrosis. J Med Chem, 53 (21): 7715-30. [PMID:20942471]

8. Paravicini TM, Chrissobolis S, Drummond GR, Sobey CG. (2004) Increased NADPH-oxidase activity and Nox4 expression during chronic hypertension is associated with enhanced cerebral vasodilatation to NADPH in vivo. Stroke, 35 (2): 584-9. [PMID:14739416]

9. Sato N, Takasaka N, Yoshida M, Tsubouchi K, Minagawa S, Araya J, Saito N, Fujita Y, Kurita Y, Kobayashi K et al.. (2016) Metformin attenuates lung fibrosis development via NOX4 suppression. Respir Res, 17 (1): 107. [PMID:27576730]

10. Shiose A, Kuroda J, Tsuruya K, Hirai M, Hirakata H, Naito S, Hattori M, Sakaki Y, Sumimoto H. (2001) A novel superoxide-producing NAD(P)H oxidase in kidney. J Biol Chem, 276 (2): 1417-23. [PMID:11032835]

11. Sorescu D, Weiss D, Lassègue B, Clempus RE, Szöcs K, Sorescu GP, Valppu L, Quinn MT, Lambeth JD, Vega JD et al.. (2002) Superoxide production and expression of nox family proteins in human atherosclerosis. Circulation, 105 (12): 1429-35. [PMID:11914250]

12. Xu Q, Kulkarni AA, Sajith AM, Hussein D, Brown D, Güner OF, Reddy MD, Watkins EB, Lassègue B, Griendling KK et al.. (2018) Design, synthesis, and biological evaluation of inhibitors of the NADPH oxidase, Nox4. Bioorg Med Chem, 26 (5): 989-998. [PMID:29426628]

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