Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK9T5O3)

• DOT Name: Endothelin-1 receptor (EDNRA)
• Synonyms: Endothelin receptor type A; ET-A; ETA-R; hET-AR
• Gene Name: EDNRA
• Related Disease: Mandibulofacial dysostosis with alopecia
• UniProt ID: EDNRA_HUMAN
• PDB ID: 8HCQ
• Pfam ID: PF00001
• Sequence:
  METLCLRASFWLALVGCVISDNPERYSTNLSNHVDDFTTFRGTELSFLVTTHQPTNLVLP
  SNGSMHNYCPQQTKITSAFKYINTVISCTIFIVGMVGNATLLRIIYQNKCMRNGPNALIA
  SLALGDLIYVVIDLPINVFKLLAGRWPFDHNDFGVFLCKLFPFLQKSSVGITVLNLCALS
  VDRYRAVASWSRVQGIGIPLVTAIEIVSIWILSFILAIPEAIGFVMVPFEYRGEQHKTCM
  LNATSKFMEFYQDVKDWWLFGFYFCMPLVCTAIFYTLMTCEMLNRRNGSLRIALSEHLKQ
  RREVAKTVFCLVVIFALCWFPLHLSRILKKTVYNEMDKNRCELLSFLLLMDYIGINLATM
  NSCINPIALYFVSKKFKNCFQSCLCCCCYQSKSLMTSVPMNGTSIQWKNHDQNNHNTDRS
  SHKDSMN
• Function: Receptor for endothelin-1. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of binding affinities for ET-A is: ET1 > ET2 >> ET3.
• Tissue Specificity: Isoform 1, isoform 3 and isoform 4 are expressed in a variety of tissues, with highest levels in the aorta and cerebellum, followed by lung, atrium and cerebral cortex, lower levels in the placenta, kidney, adrenal gland, duodenum, colon, ventricle and liver but no expression in umbilical vein endothelial cells. Within the placenta, isoform 1, isoform 2, isoform 3 and isoform 4 are expressed in the villi and stem villi vessels.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Vascular smooth muscle contraction (hsa04270)
  Renin secretion (hsa04924)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Peptide ligand-binding receptors (R-HSA-375276)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mandibulofacial dysostosis with alopecia	DISBGVUE	Definitive	Autosomal dominant	[1]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Endothelin-1 receptor (EDNRA) affects the response to substance of Cisplatin.	[23]
Fluorouracil	DMUM7HZ	Approved	Endothelin-1 receptor (EDNRA) affects the response to substance of Fluorouracil.	[23]
DTI-015	DMXZRW0	Approved	Endothelin-1 receptor (EDNRA) affects the response to substance of DTI-015.	[24]

25 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 Endothelin-1 receptor (EDNRA).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Endothelin-1 receptor (EDNRA).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Endothelin-1 receptor (EDNRA).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Endothelin-1 receptor (EDNRA).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Endothelin-1 receptor (EDNRA).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Endothelin-1 receptor (EDNRA).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Endothelin-1 receptor (EDNRA).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Endothelin-1 receptor (EDNRA).	[9]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Endothelin-1 receptor (EDNRA).	[10]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Endothelin-1 receptor (EDNRA).	[11]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Endothelin-1 receptor (EDNRA).	[8]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Endothelin-1 receptor (EDNRA).	[13]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Endothelin-1 receptor (EDNRA).	[14]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Endothelin-1 receptor (EDNRA).	[15]
Fructose	DM43AN2	Approved	Fructose increases the expression of Endothelin-1 receptor (EDNRA).	[16]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Endothelin-1 receptor (EDNRA).	[10]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Endothelin-1 receptor (EDNRA).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Endothelin-1 receptor (EDNRA).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Endothelin-1 receptor (EDNRA).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Endothelin-1 receptor (EDNRA).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Endothelin-1 receptor (EDNRA).	[19]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Endothelin-1 receptor (EDNRA).	[20]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Endothelin-1 receptor (EDNRA).	[21]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the expression of Endothelin-1 receptor (EDNRA).	[22]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Endothelin-1 receptor (EDNRA).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Endothelin-1 receptor (EDNRA).	[12]

References

• [1] Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia. Am J Hum Genet. 2015 Apr 2;96(4):519-31. doi: 10.1016/j.ajhg.2015.01.015. Epub 2015 Mar 12.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Functional cardiotoxicity assessment of cosmetic compounds using human-induced pluripotent stem cell-derived cardiomyocytes. Arch Toxicol. 2018 Jan;92(1):371-381.
• [6] ETAR antagonist ZD4054 exhibits additive effects with aromatase inhibitors and fulvestrant in breast cancer therapy, and improves in vivo efficacy of anastrozole. Breast Cancer Res Treat. 2010 Sep;123(2):345-57. doi: 10.1007/s10549-009-0644-2. Epub 2009 Nov 27.
• [7] 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.
• [8] 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.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] 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.
• [11] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [12] 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.
• [13] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [14] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [15] Molecular analysis of cocaine-induced endothelial dysfunction: role of endothelin-1 and nitric oxide. Cardiovasc Toxicol. 2008 Dec;8(4):161-71.
• [16] Non-nutritional sweeteners effects on endothelial vascular function. Toxicol In Vitro. 2020 Feb;62:104694. doi: 10.1016/j.tiv.2019.104694. Epub 2019 Oct 23.
• [17] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [18] 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.
• [19] 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.
• [20] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [21] An in vitro strategy using multiple human induced pluripotent stem cell-derived models to assess the toxicity of chemicals: A case study on paraquat. Toxicol In Vitro. 2022 Jun;81:105333. doi: 10.1016/j.tiv.2022.105333. Epub 2022 Feb 16.
• [22] Agmatine mitigates palmitate (PA)-induced mitochondrial and metabolic dysfunction in microvascular endothelial cells. Hum Exp Toxicol. 2022 Jan-Dec;41:9603271221110857. doi: 10.1177/09603271221110857.
• [23] Therapeutic targeting of the endothelin a receptor in human nasopharyngeal carcinoma. Cancer Sci. 2006 Dec;97(12):1388-95. doi: 10.1111/j.1349-7006.2006.00333.x. Epub 2006 Oct 9.
• [24] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.