Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS8N7MK)

• DOT Name: Nectin-3 (NECTIN3)
• Synonyms: CDw113; Nectin cell adhesion molecule 3; Poliovirus receptor-related protein 3; CD antigen CD113
• Gene Name: NECTIN3
• Related Disease:
  Cognitive impairment
  Advanced cancer
  Endometriosis
  Epithelial ovarian cancer
  Lung adenocarcinoma
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic adenocarcinoma
  Pancreatic cancer
  Spermatogenic failure 6
  Tauopathy
  Breast cancer
  Breast carcinoma
• UniProt ID: NECT3_HUMAN
• PDB ID: 4FOM
• Pfam ID: PF08205 ; PF07686
• Sequence:
  MARTLRPSPLCPGGGKAQLSSASLLGAGLLLQPPTPPPLLLLLFPLLLFSRLCGALAGPI
  IVEPHVTAVWGKNVSLKCLIEVNETITQISWEKIHGKSSQTVAVHHPQYGFSVQGEYQGR
  VLFKNYSLNDATITLHNIGFSDSGKYICKAVTFPLGNAQSSTTVTVLVEPTVSLIKGPDS
  LIDGGNETVAAICIAATGKPVAHIDWEGDLGEMESTTTSFPNETATIISQYKLFPTRFAR
  GRRITCVVKHPALEKDIRYSFILDIQYAPEVSVTGYDGNWFVGRKGVNLKCNADANPPPF
  KSVWSRLDGQWPDGLLASDNTLHFVHPLTFNYSGVYICKVTNSLGQRSDQKVIYISDPPT
  TTTLQPTIQWHPSTADIEDLATEPKKLPFPLSTLATIKDDTIATIIASVVGGALFIVLVS
  VLAGIFCYRRRRTFRGDYFAKNYIPPSDMQKESQIDVLQQDELDSYPDSVKKENKNPVNN
  LIRKDYLEEPEKTQWNNVENLNRFERPMDYYEDLKMGMKFVSDEHYDENEDDLVSHVDGS
  VISRREWYV
• Function: Plays a role in cell-cell adhesion through heterophilic trans-interactions with nectin-like proteins or nectins, such as trans-interaction with NECTIN2 at Sertoli-spermatid junctions. Trans-interaction with PVR induces activation of CDC42 and RAC small G proteins through common signaling molecules such as SRC and RAP1. Also involved in the formation of cell-cell junctions, including adherens junctions and synapses. Induces endocytosis-mediated down-regulation of PVR from the cell surface, resulting in reduction of cell movement and proliferation. Plays a role in the morphology of the ciliary body.
• Tissue Specificity: Predominantly expressed in testis and placenta as well as in many cell lines, including epithelial cell lines.
• KEGG Pathway:
  Cell adhesion molecules (hsa04514)
  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

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cognitive impairment	DISH2ERD	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Endometriosis	DISX1AG8	Strong	Biomarker	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[2]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[2]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[2]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[2]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Biomarker	[2]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[4]
Spermatogenic failure 6	DISCK87Z	Strong	Biomarker	[5]
Tauopathy	DISY2IPA	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[7]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Nectin-3 (NECTIN3).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Nectin-3 (NECTIN3).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Nectin-3 (NECTIN3).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nectin-3 (NECTIN3).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Nectin-3 (NECTIN3).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Nectin-3 (NECTIN3).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Nectin-3 (NECTIN3).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Nectin-3 (NECTIN3).	[14]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Nectin-3 (NECTIN3).	[15]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the expression of Nectin-3 (NECTIN3).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Nectin-3 (NECTIN3).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Nectin-3 (NECTIN3).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Nectin-3 (NECTIN3).	[19]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Nectin-3 (NECTIN3).	[21]

References

• [1] Nectin-3 modulates the structural plasticity of dentate granule cells and long-term memory.Transl Psychiatry. 2017 Sep 5;7(9):e1228. doi: 10.1038/tp.2017.196.
• [2] Nectin-3 is a new biomarker that mediates the upregulation of MMP2 and MMP9 in ovarian cancer cells.Biomed Pharmacother. 2019 Feb;110:139-144. doi: 10.1016/j.biopha.2018.11.020. Epub 2018 Nov 20.
• [3] Eutopic endometrium and peritoneal, ovarian and colorectal endometriotic tissues express a different profile of nectin-1, -3, -4 and nectin-like molecule 2.Hum Reprod. 2012 Nov;27(11):3179-86. doi: 10.1093/humrep/des304. Epub 2012 Aug 27.
• [4] Nectin expression in pancreatic adenocarcinoma: nectin-3 is associated with a poor prognosis.Surg Today. 2015 Apr;45(4):487-94. doi: 10.1007/s00595-015-1126-2. Epub 2015 Feb 19.
• [5] 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.
• [6] Early structural and functional defects in synapses and myelinated axons in stratum lacunosum moleculare in two preclinical models for tauopathy.PLoS One. 2014 Feb 3;9(2):e87605. doi: 10.1371/journal.pone.0087605. eCollection 2014.
• [7] The expression of the Nectin complex in human breast cancer and the role of Nectin-3 in the control of tight junctions during metastasis.PLoS One. 2013 Dec 26;8(12):e82696. doi: 10.1371/journal.pone.0082696. eCollection 2013.
• [8] 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.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [14] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [15] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [16] 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.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] 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.
• [20] 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.
• [21] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.