Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAUW7L2)

• DOT Name: Neutrophil cytosol factor 2 (NCF2)
• Synonyms: NCF-2; 67 kDa neutrophil oxidase factor; NADPH oxidase activator 2; Neutrophil NADPH oxidase factor 2; p67-phox
• Gene Name: NCF2
• Related Disease:
  Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2
  Rheumatoid arthritis
  Amyloidosis
  Arteriosclerosis
  Atherosclerosis
  Autoimmune disease
  Clear cell renal carcinoma
  Coeliac disease
  Fatty liver disease
  Friedreich's ataxia
  Glioma
  Granulomatous disease, chronic, X-linked
  High blood pressure
  Hyperlipidemia
  Inflammatory bowel disease
  Irritable bowel syndrome
  Lupus
  Myositis disease
  Nephropathy
  Renal fibrosis
  Systemic sclerosis
  Tuberculosis
  Chronic granulomatous disease
  Arthritis
  Coronary heart disease
  Gastric cancer
  Obesity
  Pneumonia
  Stomach cancer
  Systemic lupus erythematosus
• UniProt ID: NCF2_HUMAN
• PDB ID: 1E96; 1HH8; 1K4U; 1OEY; 1WM5; 2DMO
• Pfam ID: PF00564 ; PF00018 ; PF13181
• Sequence:
  MSLVEAISLWNEGVLAADKKDWKGALDAFSAVQDPHSRICFNIGCMYTILKNMTEAEKAF
  TRSINRDKHLAVAYFQRGMLYYQTEKYDLAIKDLKEALIQLRGNQLIDYKILGLQFKLFA
  CEVLYNIAFMYAKKEEWKKAEEQLALATSMKSEPRHSKIDKAMECVWKQKLYEPVVIPVG
  KLFRPNERQVAQLAKKDYLGKATVVASVVDQDSFSGFAPLQPQAAEPPPRPKTPEIFRAL
  EGEAHRVLFGFVPETKEELQVMPGNIVFVLKKGNDNWATVMFNGQKGLVPCNYLEPVELR
  IHPQQQPQEESSPQSDIPAPPSSKAPGRPQLSPGQKQKEEPKEVKLSVPMPYTLKVHYKY
  TVVMKTQPGLPYSQVRDMVSKKLELRLEHTKLSYRPRDSNELVPLSEDSMKDAWGQVKNY
  CLTLWCENTVGDQGFPDEPKESEKADANNQTTEPQLKKGSQVEALFSYEATQPEDLEFQE
  GDIILVLSKVNEEWLEGECKGKVGIFPKVFVEDCATTDLESTRREV
• Function: NCF2, NCF1, and a membrane bound cytochrome b558 are required for activation of the latent NADPH oxidase (necessary for superoxide production).
• KEGG Pathway:
  Phagosome (hsa04145)
  Osteoclast differentiation (hsa04380)
  Neutrophil extracellular trap formation (hsa04613)
  Leukocyte transendothelial migration (hsa04670)
  Prion disease (hsa05020)
  Leishmaniasis (hsa05140)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Diabetic cardiomyopathy (hsa05415)
  Lipid and atherosclerosis (hsa05417)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  Cross-presentation of particulate exogenous antigens (phagosomes) (R-HSA-1236973)
  Detoxification of Reactive Oxygen Species (R-HSA-3299685)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  RHO GTPases Activate NADPH Oxidases (R-HSA-5668599)
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC2 GTPase cycle (R-HSA-9013404)
  RAC3 GTPase cycle (R-HSA-9013423)
  ROS and RNS production in phagocytes (R-HSA-1222556)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2	DISMS4O6	Definitive	Autosomal recessive	[1]
Rheumatoid arthritis	DISTSB4J	Definitive	Genetic Variation	[2]
Amyloidosis	DISHTAI2	Strong	Genetic Variation	[3]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[4]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[4]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[5]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[6]
Coeliac disease	DISIY60C	Strong	Genetic Variation	[7]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[8]
Friedreich's ataxia	DIS5DV35	Strong	Biomarker	[9]
Glioma	DIS5RPEH	Strong	Biomarker	[10]
Granulomatous disease, chronic, X-linked	DISNTTS3	Strong	Genetic Variation	[11]
High blood pressure	DISY2OHH	Strong	Biomarker	[12]
Hyperlipidemia	DIS61J3S	Strong	Biomarker	[13]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[14]
Irritable bowel syndrome	DIS27206	Strong	Genetic Variation	[14]
Lupus	DISOKJWA	Strong	Biomarker	[15]
Myositis disease	DISCIXF0	Strong	Genetic Variation	[2]
Nephropathy	DISXWP4P	Strong	Biomarker	[16]
Renal fibrosis	DISMHI3I	Strong	Biomarker	[17]
Systemic sclerosis	DISF44L6	Strong	Genetic Variation	[2]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[18]
Chronic granulomatous disease	DIS9ZR24	Supportive	Autosomal recessive	[19]
Arthritis	DIST1YEL	Disputed	Genetic Variation	[20]
Coronary heart disease	DIS5OIP1	Limited	Biomarker	[13]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[21]
Obesity	DIS47Y1K	Limited	Biomarker	[22]
Pneumonia	DIS8EF3M	Limited	Biomarker	[15]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[21]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[2]

23 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Neutrophil cytosol factor 2 (NCF2).	[23]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Neutrophil cytosol factor 2 (NCF2).	[24]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Neutrophil cytosol factor 2 (NCF2).	[25]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Neutrophil cytosol factor 2 (NCF2).	[26]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Neutrophil cytosol factor 2 (NCF2).	[27]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Neutrophil cytosol factor 2 (NCF2).	[28]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Neutrophil cytosol factor 2 (NCF2).	[29]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of Neutrophil cytosol factor 2 (NCF2).	[30]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Neutrophil cytosol factor 2 (NCF2).	[31]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Neutrophil cytosol factor 2 (NCF2).	[32]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Neutrophil cytosol factor 2 (NCF2).	[33]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Neutrophil cytosol factor 2 (NCF2).	[34]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Neutrophil cytosol factor 2 (NCF2).	[35]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Neutrophil cytosol factor 2 (NCF2).	[36]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Neutrophil cytosol factor 2 (NCF2).	[37]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of Neutrophil cytosol factor 2 (NCF2).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Neutrophil cytosol factor 2 (NCF2).	[29]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Neutrophil cytosol factor 2 (NCF2).	[40]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Neutrophil cytosol factor 2 (NCF2).	[41]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Neutrophil cytosol factor 2 (NCF2).	[42]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Neutrophil cytosol factor 2 (NCF2).	[43]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Neutrophil cytosol factor 2 (NCF2).	[44]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Neutrophil cytosol factor 2 (NCF2).	[45]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate affects the localization of Neutrophil cytosol factor 2 (NCF2).	[39]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Beta-D-Glucose	DM5IHYP	Investigative	Beta-D-Glucose increases the phosphorylation of Neutrophil cytosol factor 2 (NCF2).	[46]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases.Ann Rheum Dis. 2019 Mar;78(3):311-319. doi: 10.1136/annrheumdis-2018-214127. Epub 2018 Dec 20.
• [3] Enalapril Alone or Co-Administered with Losartan Rescues Cerebrovascular Dysfunction, but not Mnemonic Deficits or Amyloidosis in a Mouse Model of Alzheimer's Disease.J Alzheimers Dis. 2016;51(4):1183-95. doi: 10.3233/JAD-150868.
• [4] Nox activator 1: a potential target for modulation of vascular reactive oxygen species in atherosclerotic arteries.Circulation. 2010 Feb 2;121(4):549-59. doi: 10.1161/CIRCULATIONAHA.109.908319. Epub 2010 Jan 18.
• [5] A novel mutation in NCF2 associated with autoimmune disease and a solitary late-onset infection.Clin Immunol. 2015 Dec;161(2):128-30. doi: 10.1016/j.clim.2015.08.003. Epub 2015 Aug 10.
• [6] Role of inflammatory related gene expression in clear cell renal cell carcinoma development and clinical outcomes.J Urol. 2011 Nov;186(5):2071-7. doi: 10.1016/j.juro.2011.06.049. Epub 2011 Sep 23.
• [7] Functional implications of disease-specific variants in loci jointly associated with coeliac disease and rheumatoid arthritis.Hum Mol Genet. 2016 Jan 1;25(1):180-90. doi: 10.1093/hmg/ddv455. Epub 2015 Nov 5.
• [8] Lipidomic and transcriptomic analysis of western diet-induced nonalcoholic steatohepatitis (NASH) in female Ldlr -/- mice.PLoS One. 2019 Apr 3;14(4):e0214387. doi: 10.1371/journal.pone.0214387. eCollection 2019.
• [9] Lymphoblast Oxidative Stress Genes as Potential Biomarkers of Disease Severity and Drug Effect in Friedreich's Ataxia.PLoS One. 2016 Apr 14;11(4):e0153574. doi: 10.1371/journal.pone.0153574. eCollection 2016.
• [10] MicroRNA-524 inhibits the progress of glioma via the direct targeting of NCF2.Am J Transl Res. 2019 Mar 15;11(3):1605-1615. eCollection 2019.
• [11] Chronic granulamatous disease: Two decades of experience from a paediatric immunology unit in a country with high rate of consangineous marriages.Scand J Immunol. 2019 Feb;89(2):e12737. doi: 10.1111/sji.12737. Epub 2019 Jan 23.
• [12] NOX2-derived reactive oxygen species in immune cells exacerbates salt-sensitive hypertension.Free Radic Biol Med. 2020 Jan;146:333-339. doi: 10.1016/j.freeradbiomed.2019.11.014. Epub 2019 Nov 12.
• [13] NCF2, MYO1F, S1PR4, and FCN1 as potential noninvasive diagnostic biomarkers in patients with obstructive coronary artery: A weighted gene co-expression network analysis.J Cell Biochem. 2019 Oct;120(10):18219-18235. doi: 10.1002/jcb.29128. Epub 2019 Jun 27.
• [14] NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2.Gut. 2012 Jul;61(7):1028-35. doi: 10.1136/gutjnl-2011-300078. Epub 2011 Sep 7.
• [15] Haploinsufficiency of NADPH Oxidase Subunit Neutrophil Cytosolic Factor 2 Is Sufficient to Accelerate Full-Blown Lupus in NZM 2328 Mice.Arthritis Rheumatol. 2017 Aug;69(8):1647-1660. doi: 10.1002/art.40141. Epub 2017 Jul 5.
• [16] Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy.Kidney Blood Press Res. 2018;43(3):987-999. doi: 10.1159/000490688. Epub 2018 Jun 15.
• [17] Increased expression of NAD(P)H oxidase subunit p67(phox) in the renal medulla contributes to excess oxidative stress and salt-sensitive hypertension.Cell Metab. 2012 Feb 8;15(2):201-8. doi: 10.1016/j.cmet.2012.01.003.
• [18] A Novel Genetic Variation in NCF2, the Core Component of NADPH Oxidase, Contributes to the Susceptibility of Tuberculosis in Western Chinese Han Population.DNA Cell Biol. 2020 Jan;39(1):57-62. doi: 10.1089/dna.2019.5082. Epub 2019 Dec 2.
• [19] Chronic Granulomatous Disease. 2012 Aug 9 [updated 2022 Apr 21]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [20] The association between single-nucleotide polymorphisms of NCF2 and systemic lupus erythematosus in Chinese mainland population.Clin Rheumatol. 2011 Apr;30(4):521-7. doi: 10.1007/s10067-010-1567-3. Epub 2010 Sep 15.
• [21] LINC01410-miR-532-NCF2-NF-kB feedback loop promotes gastric cancer angiogenesis and metastasis.Oncogene. 2018 May;37(20):2660-2675. doi: 10.1038/s41388-018-0162-y. Epub 2018 Feb 27.
• [22] Flow-induced remodeling in resistance arteries from obese Zucker rats is associated with endothelial dysfunction.Hypertension. 2007 Jul;50(1):248-54. doi: 10.1161/HYPERTENSIONAHA.107.088716. Epub 2007 May 21.
• [23] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [24] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [25] Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
• [26] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [27] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [28] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [29] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [30] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [31] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [32] NADPH oxidase-produced superoxide mediates EGFR transactivation by c-Src in arsenic trioxide-stimulated human keratinocytes. Arch Toxicol. 2012 Jun;86(6):935-45. doi: 10.1007/s00204-012-0856-9. Epub 2012 Apr 25.
• [33] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [34] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [35] Activation of peroxisome proliferator-activated receptor gamma contributes to the survival of T lymphoma cells by affecting cellular metabolism. Am J Pathol. 2007 Feb;170(2):722-32. doi: 10.2353/ajpath.2007.060651.
• [36] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [37] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [38] Identification of retinoid-modulated proteins in squamous carcinoma cells using high-throughput immunoblotting. Cancer Res. 2004 Apr 1;64(7):2439-48. doi: 10.1158/0008-5472.can-03-2643.
• [39] Cigarette smoke impairs neutrophil respiratory burst activation by aldehyde-induced thiol modifications. Toxicology. 2001 Mar 7;160(1-3):207-17. doi: 10.1016/s0300-483x(00)00450-9.
• [40] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [41] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [42] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [43] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [44] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [45] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.
• [46] Cytosolic phospholipase A2 (cPLA2) regulation of human monocyte NADPH oxidase activity. cPLA2 affects translocation but not phosphorylation of p67(phox) and p47(phox). J Biol Chem. 2002 Jul 12;277(28):25385-92. doi: 10.1074/jbc.M203630200. Epub 2002 May 6.