Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIE0W6O)

DOT Name	Nectin-2 (NECTIN2)
Synonyms	Herpes virus entry mediator B; Herpesvirus entry mediator B; HveB; Nectin cell adhesion molecule 2; Poliovirus receptor-related protein 2; CD antigen CD112
Gene Name	NECTIN2
Related Disease	Acute myelogenous leukaemia ( ) B-cell neoplasm ( ) Acute monocytic leukemia ( ) Age-related macular degeneration ( ) Arteriosclerosis ( ) Autoimmune disease ( ) Breast cancer ( ) Breast carcinoma ( ) Breast neoplasm ( ) Coronary heart disease ( ) Endometrial carcinoma ( ) Epithelial ovarian cancer ( ) Esophageal squamous cell carcinoma ( ) Familial Alzheimer disease ( ) Herpes simplex infection ( ) Lung cancer ( ) Lung carcinoma ( ) Mantle cell lymphoma ( ) Matthew-Wood syndrome ( ) Neoplasm ( ) Non-hodgkin lymphoma ( ) Non-insulin dependent diabetes ( ) Ovarian cancer ( ) Ovarian neoplasm ( ) Parkinson disease ( ) Primary cutaneous peripheral T-cell lymphoma not otherwise specified ( ) Prostate carcinoma ( ) Prostate neoplasm ( ) Spermatogenic failure 6 ( ) Systemic lupus erythematosus ( ) Systemic sclerosis ( ) T-cell lymphoma ( ) Dementia ( ) Ewing sarcoma ( ) leukaemia ( ) Leukemia ( ) Poliomyelitis ( ) Advanced cancer ( ) Alzheimer disease ( ) Atherosclerosis ( ) B-cell lymphoma ( ) Carcinoma of liver and intrahepatic biliary tract ( ) Liver cancer ( ) Prostate cancer ( ) Urinary bladder cancer ( ) Urinary bladder neoplasm ( )
UniProt ID	NECT2_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	3R0N; 4DFH; 4DFI; 4HZA; 5V52
Pfam ID	PF08205 ; PF07686
Sequence	MARAAALLPSRSPPTPLLWPLLLLLLLETGAQDVRVQVLPEVRGQLGGTVELPCHLLPPV PGLYISLVTWQRPDAPANHQNVAAFHPKMGPSFPSPKPGSERLSFVSAKQSTGQDTEAEL QDATLALHGLTVEDEGNYTCEFATFPKGSVRGMTWLRVIAKPKNQAEAQKVTFSQDPTTV ALCISKEGRPPARISWLSSLDWEAKETQVSGTLAGTVTVTSRFTLVPSGRADGVTVTCKV EHESFEEPALIPVTLSVRYPPEVSISGYDDNWYLGRTDATLSCDVRSNPEPTGYDWSTTS GTFPTSAVAQGSQLVIHAVDSLFNTTFVCTVTNAVGMGRAEQVIFVRETPNTAGAGATGG IIGGIIAAIIATAVAATGILICRQQRKEQTLQGAEEDEDLEGPPSYKPPTPKAKLEAQEM PSQLFTLGASEHSPLKTPYFDAGASCTEQEMPRYHELPTLEERSGPLHPGATSLGSPIPV PPGPPAVEDVSLDLEDEEGEEEEEYLDKINPIYDALSYSSPSDSYQGKGFVMSRAMYV
Function	Modulator of T-cell signaling. Can be either a costimulator of T-cell function, or a coinhibitor, depending on the receptor it binds to. Upon binding to CD226, stimulates T-cell proliferation and cytokine production, including that of IL2, IL5, IL10, IL13, and IFNG. Upon interaction with PVRIG, inhibits T-cell proliferation. These interactions are competitive. Probable cell adhesion protein ; (Microbial infection) Acts as a receptor for herpes simplex virus 1 (HHV-1) mutant Rid1, herpes simplex virus 1 (HHV-2) and pseudorabies virus (PRV).
Tissue Specificity	Ubiquitous.
KEGG Pathway	Virion - Herpesvirus (hsa03266 ) Cell adhesion molecules (hsa04514 ) Adherens junction (hsa04520 ) Herpes simplex virus 1 infection (hsa05168 )
Reactome Pathway	Adherens junctions interactions (R-HSA-418990 ) Nectin/Necl trans heterodimerization (R-HSA-420597 ) Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933 )

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Acute myelogenous leukaemia	DISCSPTN	Definitive	Biomarker	[1]
B-cell neoplasm	DISVY326	Definitive	Biomarker	[2]
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[3]
Age-related macular degeneration	DIS0XS2C	Strong	Genetic Variation	[4]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[5]
Autoimmune disease	DISORMTM	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Therapeutic	[7]
Breast carcinoma	DIS2UE88	Strong	Therapeutic	[7]
Breast neoplasm	DISNGJLM	Strong	Therapeutic	[7]
Coronary heart disease	DIS5OIP1	Strong	Biomarker	[8]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[9]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[10]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[11]
Familial Alzheimer disease	DISE75U4	Strong	Biomarker	[12]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[13]
Lung cancer	DISCM4YA	Strong	Biomarker	[14]
Lung carcinoma	DISTR26C	Strong	Biomarker	[14]
Mantle cell lymphoma	DISFREOV	Strong	Altered Expression	[15]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[16]
Neoplasm	DISZKGEW	Strong	Altered Expression	[10]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Altered Expression	[15]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[17]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[10]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[10]
Parkinson disease	DISQVHKL	Strong	Biomarker	[18]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	DIS5OHQF	Strong	Biomarker	[19]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[20]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[20]
Spermatogenic failure 6	DISCK87Z	Strong	Biomarker	[21]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[22]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[23]
T-cell lymphoma	DISSXRTQ	Strong	Altered Expression	[24]
Dementia	DISXL1WY	moderate	Genetic Variation	[25]
Ewing sarcoma	DISQYLV3	moderate	Altered Expression	[26]
leukaemia	DISS7D1V	moderate	Altered Expression	[26]
Leukemia	DISNAKFL	moderate	Altered Expression	[26]
Poliomyelitis	DISANFJN	moderate	Altered Expression	[27]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[9]
Alzheimer disease	DISF8S70	Limited	Genetic Variation	[28]
Atherosclerosis	DISMN9J3	Limited	Biomarker	[5]
B-cell lymphoma	DISIH1YQ	Limited	Biomarker	[24]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[29]
Liver cancer	DISDE4BI	Limited	Biomarker	[29]
Prostate cancer	DISF190Y	Limited	Altered Expression	[20]
Urinary bladder cancer	DISDV4T7	Limited	Biomarker	[30]
Urinary bladder neoplasm	DIS7HACE	Limited	Biomarker	[30]
------------------------------------------------------------------------------------


⏷ Show the Full List of 46 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Nectin-2 (NECTIN2) affects the response to substance of Methotrexate.	[45]
------------------------------------------------------------------------------------

12 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 Nectin-2 (NECTIN2).	[31]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Nectin-2 (NECTIN2).	[32]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nectin-2 (NECTIN2).	[33]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Nectin-2 (NECTIN2).	[34]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nectin-2 (NECTIN2).	[35]
Selenium	DM25CGV	Approved	Selenium increases the expression of Nectin-2 (NECTIN2).	[36]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Nectin-2 (NECTIN2).	[37]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Nectin-2 (NECTIN2).	[37]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Nectin-2 (NECTIN2).	[39]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Nectin-2 (NECTIN2).	[42]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Nectin-2 (NECTIN2).	[43]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Nectin-2 (NECTIN2).	[44]
------------------------------------------------------------------------------------


⏷ Show the Full List of 12 Drug(s)

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Nectin-2 (NECTIN2).	[38]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Nectin-2 (NECTIN2).	[40]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Nectin-2 (NECTIN2).	[41]
------------------------------------------------------------------------------------

References

1	Monitoring TIGIT/DNAM-1 and PVR/PVRL2 Immune Checkpoint Expression Levels in Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia.Biol Blood Marrow Transplant. 2019 May;25(5):861-867. doi: 10.1016/j.bbmt.2019.01.013. Epub 2019 Jan 11.
2	Gene signature in Alzheimer's disease and environmental factors: the virus chronicle.J Alzheimers Dis. 2011;27(4):809-17. doi: 10.3233/JAD-2011-110755.
3	Immune checkpoints PVR and PVRL2 are prognostic markers in AML and their blockade represents a new therapeutic option.Oncogene. 2018 Sep;37(39):5269-5280. doi: 10.1038/s41388-018-0288-y. Epub 2018 May 31.
4	Insights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis.PLoS One. 2013;8(1):e53830. doi: 10.1371/journal.pone.0053830. Epub 2013 Jan 11.
5	Poliovirus Receptor-Related 2: A Cholesterol-Responsive Gene Affecting Atherosclerosis Development by Modulating Leukocyte Migration.Arterioscler Thromb Vasc Biol. 2017 Mar;37(3):534-542. doi: 10.1161/ATVBAHA.116.308715. Epub 2017 Jan 5.
6	Structural, mutational and biophysical studies reveal a canonical mode of molecular recognition between immune receptor TIGIT and nectin-2.Mol Immunol. 2017 Jan;81:151-159. doi: 10.1016/j.molimm.2016.12.003. Epub 2016 Dec 12.
7	Nectin-2 is a potential target for antibody therapy of breast and ovarian cancers.Mol Cancer. 2013 Jun 12;12:60. doi: 10.1186/1476-4598-12-60.
8	An integrated genomic-transcriptomic approach supports a role for the proto-oncogene BCL3 in atherosclerosis.Thromb Haemost. 2015 Mar;113(3):655-63. doi: 10.1160/TH14-05-0466. Epub 2014 Nov 6.
9	PVRIG and PVRL2 Are Induced in Cancer and Inhibit CD8(+) T-cell Function.Cancer Immunol Res. 2019 Feb;7(2):257-268. doi: 10.1158/2326-6066.CIR-18-0442. Epub 2019 Jan 18.
10	Nectin-2 in ovarian cancer: How is it expressed and what might be its functional role?.Cancer Sci. 2019 Jun;110(6):1872-1882. doi: 10.1111/cas.13992. Epub 2019 May 2.
11	Elevated Nectin-2 expression is involved in esophageal squamous cell carcinoma by promoting cell migration and invasion.Oncol Lett. 2018 Apr;15(4):4731-4736. doi: 10.3892/ol.2018.7953. Epub 2018 Feb 5.
12	Hidden heterogeneity in Alzheimer's disease: Insights from genetic association studies and other analyses.Exp Gerontol. 2018 Jul 1;107:148-160. doi: 10.1016/j.exger.2017.10.020. Epub 2017 Oct 26.
13	Genome-Wide Association and Mechanistic Studies Indicate That Immune Response Contributes to Alzheimer's Disease Development.Front Genet. 2018 Sep 24;9:410. doi: 10.3389/fgene.2018.00410. eCollection 2018.
14	Serum nectin-2 and nectin-4 are diagnostic in lung cancer: which is superior?.Wien Klin Wochenschr. 2019 Sep;131(17-18):419-426. doi: 10.1007/s00508-019-01537-4. Epub 2019 Aug 22.
15	TIGIT and PD-1 Mark Intratumoral T Cells with Reduced Effector Function in B-cell Non-Hodgkin Lymphoma.Cancer Immunol Res. 2019 Mar;7(3):355-362. doi: 10.1158/2326-6066.CIR-18-0351. Epub 2019 Jan 18.
16	The Clinical and Pathological Significance of Nectin-2 and DDX3 Expression in Pancreatic Ductal Adenocarcinomas.Dis Markers. 2015;2015:379568. doi: 10.1155/2015/379568. Epub 2015 Jul 30.
17	Multi-ethnic genome-wide association study identifies novel locus for type 2 diabetes susceptibility.Eur J Hum Genet. 2016 Aug;24(8):1175-80. doi: 10.1038/ejhg.2016.17. Epub 2016 May 18.
18	Identification of candidate genes for Parkinson's disease through blood transcriptome analysis in LRRK2-G2019S carriers, idiopathic cases, and controls.Neurobiol Aging. 2015 Feb;36(2):1105-9. doi: 10.1016/j.neurobiolaging.2014.10.039. Epub 2014 Nov 5.
19	Peripheral T-cell lymphoma cell line T8ML-1 highlights conspicuous targeting of PVRL2 by t(14;19)(q11.2;q13.3).Haematologica. 2017 Sep;102(9):e356-e359. doi: 10.3324/haematol.2017.168203. Epub 2017 Jun 28.
20	Identification of targets for prostate cancer immunotherapy.Prostate. 2019 Apr;79(5):498-505. doi: 10.1002/pros.23756. Epub 2019 Jan 6.
21	Detection of candidate nectin gene mutations in infertile men with severe teratospermia.J Assist Reprod Genet. 2017 Oct;34(10):1295-1302. doi: 10.1007/s10815-017-0985-4. Epub 2017 Jul 8.
22	Gene profiling involved in immature CD4+ T lymphocyte responsible for systemic lupus erythematosus.Mol Immunol. 2006 Mar;43(9):1497-507. doi: 10.1016/j.molimm.2005.07.039. Epub 2005 Sep 6.
23	Histone Deacetylase 5 Is Overexpressed in Scleroderma Endothelial Cells and Impairs Angiogenesis via Repression of Proangiogenic Factors.Arthritis Rheumatol. 2016 Dec;68(12):2975-2985. doi: 10.1002/art.39828.
24	Novel IGH and MYC Translocation Partners in Diffuse Large B-Cell Lymphomas.Genes Chromosomes Cancer. 2016 Dec;55(12):932-943. doi: 10.1002/gcc.22391. Epub 2016 Jul 12.
25	Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias.PLoS Genet. 2014 Sep 4;10(9):e1004606. doi: 10.1371/journal.pgen.1004606. eCollection 2014 Sep.
26	DNAM-1-based chimeric antigen receptors enhance T cell effector function and exhibit in vivo efficacy against melanoma.Cancer Immunol Immunother. 2015 Apr;64(4):409-18. doi: 10.1007/s00262-014-1648-2. Epub 2014 Dec 31.
27	In Vitro Killing of Colorectal Carcinoma Cells by Autologous Activated NK Cells is Boosted by Anti-Epidermal Growth Factor Receptor-induced ADCC Regardless of RAS Mutation Status.J Immunother. 2018 May;41(4):190-200. doi: 10.1097/CJI.0000000000000205.
28	Shared genetic architecture between metabolic traits and Alzheimer's disease: a large-scale genome-wide cross-trait analysis.Hum Genet. 2019 Mar;138(3):271-285. doi: 10.1007/s00439-019-01988-9. Epub 2019 Feb 25.
29	Integrated Genomic Comparison of Mouse Models Reveals Their Clinical Resemblance to Human Liver Cancer.Mol Cancer Res. 2018 Nov;16(11):1713-1723. doi: 10.1158/1541-7786.MCR-18-0313. Epub 2018 Aug 6.
30	Identification and validation of an 18-gene signature highly-predictive of bladder cancer metastasis.Sci Rep. 2018 Jan 10;8(1):374. doi: 10.1038/s41598-017-18773-1.
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	Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
33	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.
34	Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
35	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.
36	Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
37	Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
38	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.
39	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.
40	Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
41	DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
42	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.
43	Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
44	Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.
45	Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.