NADPH oxidase 4 | NADPH oxidases | IUPHAR/BPS Guide to PHARMACOLOGY

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NADPH oxidase 4

target has curated data in GtoImmuPdb

Target id: 3004

Nomenclature: NADPH oxidase 4

Abbreviated Name: NOX4

Family: NADPH oxidases

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 578 11q14.3 NOX4 NADPH oxidase 4
Mouse 6 578 Chromosome 7, 48.96 cM; 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
KOX | KOX-1 | RENOX
Database Links
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia

Download all structure-activity data for this target as a CSV file

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] 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] Hs Inhibition 7.1 pKi 3
pKi 7.1 (Ki 7.2x10-8 M) [3]
GKT137831 Hs Inhibition 7.0 pKi 1
pKi 7.0 (Ki 1.1x10-7 M) [1]
GKT136901 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
GO Annotations:  Associated to 1 GO processes
GO:0006954 inflammatory response TAS
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. U.S.A., 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]

How to cite this page

NADPH oxidases: NADPH oxidase 4. Last modified on 06/09/2018. Accessed on 20/08/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3004.