Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJSFW1L)

• DOT Name: Nectin-4 (NECTIN4)
• Synonyms: Ig superfamily receptor LNIR; Nectin cell adhesion molecule 4; Poliovirus receptor-related protein 4
• Gene Name: NECTIN4
• Related Disease:
  Ectodermal dysplasia-syndactyly syndrome 1
  Ectodermal dysplasia-syndactyly syndrome
• UniProt ID: NECT4_HUMAN
• PDB ID: 4FRW; 4GJT; 4JJH
• Pfam ID: PF08205 ; PF13927 ; PF07686
• Sequence:
  MPLSLGAEMWGPEAWLLLLLLLASFTGRCPAGELETSDVVTVVLGQDAKLPCFYRGDSGE
  QVGQVAWARVDAGEGAQELALLHSKYGLHVSPAYEGRVEQPPPPRNPLDGSVLLRNAVQA
  DEGEYECRVSTFPAGSFQARLRLRVLVPPLPSLNPGPALEEGQGLTLAASCTAEGSPAPS
  VTWDTEVKGTTSSRSFKHSRSAAVTSEFHLVPSRSMNGQPLTCVVSHPGLLQDQRITHIL
  HVSFLAEASVRGLEDQNLWHIGREGAMLKCLSEGQPPPSYNWTRLDGPLPSGVRVDGDTL
  GFPPLTTEHSGIYVCHVSNEFSSRDSQVTVDVLDPQEDSGKQVDLVSASVVVVGVIAALL
  FCLLVVVVVLMSRYHRRKAQQMTQKYEEELTLTRENSIRRLHSHHTDPRSQPEESVGLRA
  EGHPDSLKDNSSCSVMSEEPEGRSYSTLTTVREIETQTELLSPGSGRAEEEEDQDEGIKQ
  AMNHFVQENGTLRAKPTGNGIYINGRGHLV
• Function: Seems to be involved in cell adhesion through trans-homophilic and -heterophilic interactions, the latter including specifically interactions with NECTIN1. Does not act as receptor for alpha-herpesvirus entry into cells.; (Microbial infection) Acts as a receptor for measles virus.
• Tissue Specificity: Predominantly expressed in placenta. Not detected in normal breast epithelium but expressed in breast carcinoma.
• KEGG Pathway: Adherens junction (hsa04520)
• Reactome Pathway:
  Nectin/Necl trans heterodimerization (R-HSA-420597)
  Adherens junctions interactions (R-HSA-418990)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ectodermal dysplasia-syndactyly syndrome 1	DISVDQEA	Definitive	Autosomal recessive	[1]
Ectodermal dysplasia-syndactyly syndrome	DISZFJUT	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Nectin-4 (NECTIN4).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Nectin-4 (NECTIN4).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Nectin-4 (NECTIN4).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Nectin-4 (NECTIN4).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nectin-4 (NECTIN4).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Nectin-4 (NECTIN4).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Nectin-4 (NECTIN4).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Nectin-4 (NECTIN4).	[11]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Nectin-4 (NECTIN4).	[12]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Nectin-4 (NECTIN4).	[13]
Acocantherin	DM7JT24	Approved	Acocantherin increases the expression of Nectin-4 (NECTIN4).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Nectin-4 (NECTIN4).	[15]
UNC0379	DMD1E4J	Preclinical	UNC0379 increases the expression of Nectin-4 (NECTIN4).	[17]
PIRINIXIC ACID	DM82Y75	Preclinical	PIRINIXIC ACID decreases the expression of Nectin-4 (NECTIN4).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Nectin-4 (NECTIN4).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Nectin-4 (NECTIN4).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Nectin-4 (NECTIN4).	[20]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Nectin-4 (NECTIN4).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Nectin-4 (NECTIN4).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Nectin-4 (NECTIN4).	[16]

References

• [1] [Association of ectodermal dysplasia and syndactylia]. Ann Dermatol Venereol. 1991;118(2):107-10.
• [2] Mutations in PVRL4, encoding cell adhesion molecule nectin-4, cause ectodermal dysplasia-syndactyly syndrome. Am J Hum Genet. 2010 Aug 13;87(2):265-73. doi: 10.1016/j.ajhg.2010.07.003.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [11] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] Use of transcriptomics in hazard identification and next generation risk assessment: A case study with clothianidin. Food Chem Toxicol. 2022 Aug;166:113212. doi: 10.1016/j.fct.2022.113212. Epub 2022 Jun 8.
• [14] Ouabain impairs cell migration, and invasion and alters gene expression of human osteosarcoma U-2 OS cells. Environ Toxicol. 2017 Nov;32(11):2400-2413. doi: 10.1002/tox.22453. Epub 2017 Aug 10.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63.
• [18] Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140.
• [19] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.