Details of Drug Off-Target (DOT)

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

• DOT Name: Tumor necrosis factor receptor superfamily member 27 (EDA2R)
• Synonyms: X-linked ectodysplasin-A2 receptor; EDA-A2 receptor
• Gene Name: EDA2R
• Related Disease:
  Sjogren syndrome
  Alopecia
  Baldness, male pattern
  Breast cancer
  Breast carcinoma
  Ectodermal dysplasia
  X-linked hypohidrotic ectodermal dysplasia
• UniProt ID: TNR27_HUMAN
• Pfam ID: PF00020
• Sequence:
  MDCQENEYWDQWGRCVTCQRCGPGQELSKDCGYGEGGDAYCTACPPRRYKSSWGHHRCQS
  CITCAVINRVQKVNCTATSNAVCGDCLPRFYRKTRIGGLQDQECIPCTKQTPTSEVQCAF
  QLSLVEADTPTVPPQEATLVALVSSLLVVFTLAFLGLFFLYCKQFFNRHCQRGGLLQFEA
  DKTAKEESLFPVPPSKETSAESQVSENIFQTQPLNPILEDDCSSTSGFPTQESFTMASCT
  SESHSHWVHSPIECTELDLQKFSSSASYTGAETLGGNTVESTGDRLELNVPFEVPSP
• Function: Receptor for EDA isoform A2, but not for EDA isoform A1. Mediates the activation of the NF-kappa-B and JNK pathways. Activation seems to be mediated by binding to TRAF3 and TRAF6.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  NF-kappa B sig.ling pathway (hsa04064)
• Reactome Pathway: TNFs bind their physiological receptors (R-HSA-5669034)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Sjogren syndrome	DISUBX7H	Definitive	Biomarker	[1]
Alopecia	DIS37HU4	Strong	Biomarker	[2]
Baldness, male pattern	DIS9C9RO	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Posttranslational Modification	[3]
Breast carcinoma	DIS2UE88	Strong	Posttranslational Modification	[3]
Ectodermal dysplasia	DISLRS4M	Strong	Biomarker	[4]
X-linked hypohidrotic ectodermal dysplasia	DISST0XM	Supportive	X-linked	[5]

2 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 Tumor necrosis factor receptor superfamily member 27 (EDA2R).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Tumor necrosis factor receptor superfamily member 27 (EDA2R).	[14]

10 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 Tumor necrosis factor receptor superfamily member 27 (EDA2R).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Tumor necrosis factor receptor superfamily member 27 (EDA2R).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Tumor necrosis factor receptor superfamily member 27 (EDA2R).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Tumor necrosis factor receptor superfamily member 27 (EDA2R).	[10]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Tumor necrosis factor receptor superfamily member 27 (EDA2R).	[11]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Tumor necrosis factor receptor superfamily member 27 (EDA2R).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Tumor necrosis factor receptor superfamily member 27 (EDA2R).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Tumor necrosis factor receptor superfamily member 27 (EDA2R).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Tumor necrosis factor receptor superfamily member 27 (EDA2R).	[16]
UNC0379	DMD1E4J	Preclinical	UNC0379 increases the expression of Tumor necrosis factor receptor superfamily member 27 (EDA2R).	[17]

References

• [1] X-linked ectodermal dysplasia receptor (XEDAR) gene silencing prevents caspase-3-mediated apoptosis in Sjgren's syndrome.Clin Exp Med. 2017 Feb;17(1):111-119. doi: 10.1007/s10238-015-0404-z. Epub 2015 Dec 11.
• [2] Investigation of the male pattern baldness major genetic susceptibility loci AR/EDA2R and 20p11 in female pattern hair loss.Br J Dermatol. 2012 Jun;166(6):1314-8. doi: 10.1111/j.1365-2133.2012.10877.x.
• [3] X-linked ectodermal dysplasia receptor is downregulated in breast cancer via promoter methylation.Clin Cancer Res. 2010 Feb 15;16(4):1140-8. doi: 10.1158/1078-0432.CCR-09-2463. Epub 2010 Feb 9.
• [4] Role of TRAF3 and -6 in the activation of the NF-kappa B and JNK pathways by X-linked ectodermal dysplasia receptor.J Biol Chem. 2002 Nov 22;277(47):44953-61. doi: 10.1074/jbc.M207923200. Epub 2002 Sep 20.
• [5] A new mutation resulting in the truncation of the TRAF6-interacting domain of XEDAR: a possible novel cause of hypohidrotic ectodermal dysplasia. J Med Genet. 2012 Aug;49(8):499-501. doi: 10.1136/jmedgenet-2012-100877.
• [6] 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.
• [7] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [8] Identification of novel biomarkers for doxorubicin-induced toxicity in human cardiomyocytes derived from pluripotent stem cells. Toxicology. 2015 Feb 3;328:102-11. doi: 10.1016/j.tox.2014.12.018. Epub 2014 Dec 18.
• [9] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [10] Prenatal arsenic exposure and shifts in the newborn proteome: interindividual differences in tumor necrosis factor (TNF)-responsive signaling. Toxicol Sci. 2014 Jun;139(2):328-37. doi: 10.1093/toxsci/kfu053. Epub 2014 Mar 27.
• [11] 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.
• [12] Genomic profiling uncovers a molecular pattern for toxicological characterization of mutagens and promutagens in vitro. Toxicol Sci. 2011 Jul;122(1):185-97.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] 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.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] 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.
• [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.