Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX007YL)

• DOT Name: Neutrophil cytosol factor 4 (NCF4)
• Synonyms: NCF-4; Neutrophil NADPH oxidase factor 4; SH3 and PX domain-containing protein 4; p40-phox; p40phox
• Gene Name: NCF4
• Related Disease:
  Advanced cancer
  Autoimmune disease
  Colorectal carcinoma
  Cystic fibrosis
  Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3
  Granulomatous disease, chronic, X-linked
  Lymphoma, non-Hodgkin, familial
  Non-hodgkin lymphoma
  Pneumonia
  Pneumonitis
  Rheumatoid arthritis
  Immune system disorder
  Chronic granulomatous disease
  Cardiac disease
  Inflammatory bowel disease
• UniProt ID: NCF4_HUMAN
• PDB ID: 1H6H; 1OEY; 1W6X; 1W70; 1Z9Q; 2DYB
• Pfam ID: PF00564 ; PF00787 ; PF00018
• Sequence:
  MAVAQQLRAESDFEQLPDDVAISANIADIEEKRGFTSHFVFVIEVKTKGGSKYLIYRRYR
  QFHALQSKLEERFGPDSKSSALACTLPTLPAKVYVGVKQEIAEMRIPALNAYMKSLLSLP
  VWVLMDEDVRIFFYQSPYDSEQVPQALRRLRPRTRKVKSVSPQGNSVDRMAAPRAEALFD
  FTGNSKLELNFKAGDVIFLLSRINKDWLEGTVRGATGIFPLSFVKILKDFPEEDDPTNWL
  RCYYYEDTISTIKDIAVEEDLSSTPLLKDLLELTRREFQREDIALNYRDAEGDLVRLLSD
  EDVALMVRQARGLPSQKRLFPWKLHITQKDNYRVYNTMP
• Function: Component of the NADPH-oxidase, a multicomponent enzyme system responsible for the oxidative burst in which electrons are transported from NADPH to molecular oxygen, generating reactive oxidant intermediates. It may be important for the assembly and/or activation of the NADPH-oxidase complex.
• Tissue Specificity: Expression is restricted to hematopoietic cells.
• KEGG Pathway:
  Phagosome (hsa04145)
  Osteoclast differentiation (hsa04380)
  Neutrophil extracellular trap formation (hsa04613)
  Leukocyte transendothelial migration (hsa04670)
  Prion disease (hsa05020)
  Leishmaniasis (hsa05140)
  Diabetic cardiomyopathy (hsa05415)
  Lipid and atherosclerosis (hsa05417)
• 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

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[3]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[4]
Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3	DIS3RJK7	Strong	Autosomal recessive	[5]
Granulomatous disease, chronic, X-linked	DISNTTS3	Strong	Genetic Variation	[6]
Lymphoma, non-Hodgkin, familial	DISCXYIZ	Strong	Genetic Variation	[7]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Genetic Variation	[7]
Pneumonia	DIS8EF3M	Strong	Biomarker	[8]
Pneumonitis	DIS88E0K	Strong	Biomarker	[8]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[2]
Immune system disorder	DISAEGPH	moderate	Biomarker	[9]
Chronic granulomatous disease	DIS9ZR24	Supportive	Autosomal recessive	[10]
Cardiac disease	DISVO1I5	Limited	Biomarker	[11]
Inflammatory bowel disease	DISGN23E	Limited	Genetic Variation	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Neutrophil cytosol factor 4 (NCF4).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Neutrophil cytosol factor 4 (NCF4).	[14]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Neutrophil cytosol factor 4 (NCF4).	[15]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Neutrophil cytosol factor 4 (NCF4).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Neutrophil cytosol factor 4 (NCF4).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Neutrophil cytosol factor 4 (NCF4).	[18]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Neutrophil cytosol factor 4 (NCF4).	[19]

References

• [1] Cell-Surface Integrins and CAR Are Both Essential for Adenovirus Type 5 Transduction of Canine Cells of Lymphocytic Origin.PLoS One. 2017 Jan 9;12(1):e0169532. doi: 10.1371/journal.pone.0169532. eCollection 2017.
• [2] A case-control study of rheumatoid arthritis identifies an associated single nucleotide polymorphism in the NCF4 gene, supporting a role for the NADPH-oxidase complex in autoimmunity.Arthritis Res Ther. 2007;9(5):R98. doi: 10.1186/ar2299.
• [3] Germline variation in NCF4, an innate immunity gene, is associated with an increased risk of colorectal cancer.Int J Cancer. 2014 Mar 15;134(6):1399-407. doi: 10.1002/ijc.28457. Epub 2013 Nov 14.
• [4] Ineffective correction of PPAR signaling in cystic fibrosis airway epithelial cells undergoing repair.Int J Biochem Cell Biol. 2016 Sep;78:361-369. doi: 10.1016/j.biocel.2016.07.035. Epub 2016 Jul 30.
• [5] Neutrophils from p40phox-/- mice exhibit severe defects in NADPH oxidase regulation and oxidant-dependent bacterial killing. J Exp Med. 2006 Aug 7;203(8):1927-37. doi: 10.1084/jem.20052069. Epub 2006 Jul 31.
• [6] 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.
• [7] Genetic polymorphisms in oxidative stress-related genes are associated with outcomes following treatment for aggressive B-cell non-Hodgkin lymphoma.Am J Hematol. 2014 Jun;89(6):639-45. doi: 10.1002/ajh.23709. Epub 2014 Apr 12.
• [8] Fibrous nanocellulose, crystalline nanocellulose, carbon nanotubes, and crocidolite asbestos elicit disparate immune responses upon pharyngeal aspiration in mice.J Immunotoxicol. 2018 Dec;15(1):12-23. doi: 10.1080/1547691X.2017.1414339.
• [9] Genetic disorders coupled to ROS deficiency.Redox Biol. 2015 Dec;6:135-156. doi: 10.1016/j.redox.2015.07.009. Epub 2015 Jul 17.
• [10] 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.
• [11] NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity. Circulation. 2005 Dec 13;112(24):3754-62.
• [12] Association between NCF4 rs4821544T/C polymorphism and inflammatory bowel disease risk in Caucasian: a meta-analysis.Inflamm Res. 2015 Oct;64(10):825-31. doi: 10.1007/s00011-015-0866-1. Epub 2015 Aug 20.
• [13] 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.
• [14] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [15] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [16] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [17] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [18] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [19] 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.