Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFZAO1G)

• DOT Name: Nephronectin (NPNT)
• Synonyms: Preosteoblast EGF-like repeat protein with MAM domain; Protein EGFL6-like
• Gene Name: NPNT
• Related Disease:
  Neoplasm
  Achalasia
  Advanced cancer
  Atopic dermatitis
  Attention deficit hyperactivity disorder
  Breast neoplasm
  Cardiovascular disease
  Chagas disease
  Esophagitis
  Gastroesophageal reflux disease
  Nephrotic syndrome
  Obesity
  Osteoporosis
  Pulmonary disease
  Pulmonary fibrosis
  Arthritis
  Autoimmune disease
  Breast cancer
  Breast carcinoma
  Gastroparesis
  Chronic obstructive pulmonary disease
  Focal segmental glomerulosclerosis
  Melanoma
  Membranous glomerulonephritis
  Metastatic malignant neoplasm
• UniProt ID: NPNT_HUMAN
• Pfam ID: PF12947 ; PF07645 ; PF00629
• Sequence:
  MDFLLALVLVSSLYLQAAAEFDGRWPRQIVSSIGLCRYGGRIDCCWGWARQSWGQCQPVC
  QPRCKHGECIGPNKCKCHPGYAGKTCNQDLNECGLKPRPCKHRCMNTYGSYKCYCLNGYM
  LMPDGSCSSALTCSMANCQYGCDVVKGQIRCQCPSPGLQLAPDGRTCVDVDECATGRASC
  PRFRQCVNTFGSYICKCHKGFDLMYIGGKYQCHDIDECSLGQYQCSSFARCYNIRGSYKC
  KCKEGYQGDGLTCVYIPKVMIEPSGPIHVPKGNGTILKGDTGNNNWIPDVGSTWWPPKTP
  YIPPIITNRPTSKPTTRPTPKPTPIPTPPPPPPLPTELRTPLPPTTPERPTTGLTTIAPA
  ASTPPGGITVDNRVQTDPQKPRGDVFIPRQPSNDLFEIFEIERGVSADDEAKDDPGVLVH
  SCNFDHGLCGWIREKDNDLHWEPIRDPAGGQYLTVSAAKAPGGKAARLVLPLGRLMHSGD
  LCLSFRHKVTGLHSGTLQVFVRKHGAHGAALWGRNGGHGWRQTQITLRGADIKSVVFKGE
  KRRGHTGEIGLDDVSLKKGHCSEER
• Function: Functional ligand of integrin alpha-8/beta-1 in kidney development. Regulates the expression of GDNF with integrin alpha-8/beta-1 which is essential for kidney development. May also play a role in the development and function of various tissues, regulating cell adhesion, spreading and survival through the binding of several integrins.
• Tissue Specificity: Expressed in kidney and lung and to a lower extent in brain, pregnant uterus, placenta, thyroid gland and blood vessels.
• KEGG Pathway: ECM-receptor interaction (hsa04512)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Achalasia	DISK845N	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Atopic dermatitis	DISTCP41	Strong	Genetic Variation	[4]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[6]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[7]
Chagas disease	DIS8KNVF	Strong	Biomarker	[3]
Esophagitis	DISHVC9B	Strong	Genetic Variation	[2]
Gastroesophageal reflux disease	DISQ8G5S	Strong	Biomarker	[8]
Nephrotic syndrome	DISSPSC2	Strong	Biomarker	[9]
Obesity	DIS47Y1K	Strong	Biomarker	[10]
Osteoporosis	DISF2JE0	Strong	Altered Expression	[11]
Pulmonary disease	DIS6060I	Strong	Genetic Variation	[12]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[13]
Arthritis	DIST1YEL	moderate	Biomarker	[14]
Autoimmune disease	DISORMTM	moderate	Biomarker	[14]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[15]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[15]
Gastroparesis	DISDW0SR	moderate	Biomarker	[16]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Genetic Variation	[17]
Focal segmental glomerulosclerosis	DISJNHH0	Limited	Altered Expression	[18]
Melanoma	DIS1RRCY	Limited	Altered Expression	[19]
Membranous glomerulonephritis	DISFSUKQ	Limited	Altered Expression	[18]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[20]

3 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 Nephronectin (NPNT).	[21]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Nephronectin (NPNT).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Nephronectin (NPNT).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Nephronectin (NPNT).	[22]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Nephronectin (NPNT).	[23]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Nephronectin (NPNT).	[24]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nephronectin (NPNT).	[25]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Nephronectin (NPNT).	[26]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Nephronectin (NPNT).	[27]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nephronectin (NPNT).	[28]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Nephronectin (NPNT).	[30]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Nephronectin (NPNT).	[31]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Nephronectin (NPNT).	[32]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Nephronectin (NPNT).	[34]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Nephronectin (NPNT).	[35]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Nephronectin (NPNT).	[36]

References

• [1] Nephronectin is Decreased in Metastatic Breast Carcinoma and Related to Metastatic Organs.Pathol Oncol Res. 2018 Jul;24(3):679-688. doi: 10.1007/s12253-017-0289-0. Epub 2017 Aug 25.
• [2] Poem Versus Laparoscopic Heller Myotomy in the Treatment of Esophageal Achalasia: A Case-Control Study from Two High Volume Centers Using the Propensity Score.J Gastrointest Surg. 2020 Mar;24(3):505-515. doi: 10.1007/s11605-019-04465-w. Epub 2019 Dec 17.
• [3] The 2018 ISDE achalasia guidelines.Dis Esophagus. 2018 Sep 1;31(9). doi: 10.1093/dote/doy071.
• [4] Is there an association between indoor allergens and the severity of atopic dermatitis?.Int J Dermatol. 2019 Apr;58(4):433-439. doi: 10.1111/ijd.14281. Epub 2018 Nov 23.
• [5] Increased attention-deficit/hyperactivity symptoms in atopic dermatitis are associated with history of antihistamine use.Allergy. 2018 Mar;73(3):615-626. doi: 10.1111/all.13326. Epub 2017 Nov 20.
• [6] A Novel Truncated Form of Nephronectin Is Present in Small Extracellular Vesicles Isolated from 66cl4 Cells.J Proteome Res. 2019 Mar 1;18(3):1237-1247. doi: 10.1021/acs.jproteome.8b00859. Epub 2019 Feb 13.
• [7] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [8] The 2years' long-term efficacy and safety of peroral endoscopic myotomy for the treatment of achalasia: a systematic review.J Cardiothorac Surg. 2019 Jan 3;14(1):1. doi: 10.1186/s13019-018-0811-9.
• [9] Nephronectin (NPNT) and the prediction of nephrotic syndrome response to steroid treatment.Eur J Hum Genet. 2018 Sep;26(9):1354-1360. doi: 10.1038/s41431-018-0182-7. Epub 2018 Jun 11.
• [10] Endothelial dysfunction is associated with impaired lung function in two independent community cohorts.Respir Med. 2018 Oct;143:123-128. doi: 10.1016/j.rmed.2018.09.009. Epub 2018 Sep 12.
• [11] NPNT is Expressed by Osteoblasts and Mediates Angiogenesis via the Activation of Extracellular Signal-regulated Kinase.Sci Rep. 2016 Oct 26;6:36210. doi: 10.1038/srep36210.
• [12] Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation.Nat Commun. 2015 Dec 4;6:8658. doi: 10.1038/ncomms9658.
• [13] Role of Nephronectin in Pathophysiology of Silicosis.Int J Mol Sci. 2019 May 26;20(10):2581. doi: 10.3390/ijms20102581.
• [14] Antibodies against nephronectin ameliorate anti-type II collagen-induced arthritis in mice.FEBS Open Bio. 2020 Jan;10(1):107-117. doi: 10.1002/2211-5463.12758. Epub 2019 Nov 24.
• [15] Nephronectin is Correlated with Poor Prognosis in Breast Cancer and Promotes Metastasis via its Integrin-Binding Motifs.Neoplasia. 2018 Apr;20(4):387-400. doi: 10.1016/j.neo.2018.02.008. Epub 2018 Mar 11.
• [16] Initial Experience with Endoscopic Pyloromyotomy, with Description and Video of Technique.J Gastrointest Surg. 2019 Aug;23(8):1706-1710. doi: 10.1007/s11605-019-04237-6. Epub 2019 May 6.
• [17] Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations.Nat Genet. 2019 Mar;51(3):494-505. doi: 10.1038/s41588-018-0342-2. Epub 2019 Feb 25.
• [18] Podocytes regulate the glomerular basement membrane protein nephronectin by means ofmiR-378a-3p in glomerular diseases.Kidney Int. 2017 Oct;92(4):836-849. doi: 10.1016/j.kint.2017.03.005. Epub 2017 May 3.
• [19] The emerging role of NPNT in tissue injury repair and bone homeostasis.J Cell Physiol. 2018 Mar;233(3):1887-1894. doi: 10.1002/jcp.26013. Epub 2017 Jun 16.
• [20] NPNT promotes early-stage bone metastases in breast cancer by regulation of the osteogenic niche.J Bone Oncol. 2018 Sep 27;13:91-96. doi: 10.1016/j.jbo.2018.09.006. eCollection 2018 Nov.
• [21] 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.
• [22] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [23] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [24] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [25] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [26] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [27] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [28] 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.
• [29] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [30] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [31] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [32] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [33] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [34] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [35] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [36] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.