Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN7Q9BE)

• DOT Name: Endothelin-3 (EDN3)
• Synonyms: ET-3; Preproendothelin-3; PPET3
• Gene Name: EDN3
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Bacteremia
  Breast cancer
  Breast carcinoma
  Central hypoventilation syndrome, congenital
  Chronic renal failure
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  End-stage renal disease
  Glioblastoma multiforme
  Haddad syndrome
  High blood pressure
  HIV infectious disease
  Hypotension
  Interstitial nephritis
  Lung adenocarcinoma
  Neoplasm
  Waardenburg syndrome
  Waardenburg syndrome type 4A
  Waardenburg syndrome type 4B
  Achondroplasia
  Hirschsprung disease
  Hirschsprung disease, susceptibility to, 4
  Waardenburg-Shah syndrome
  Waardenburg syndrome type 2
  Melanoma
  Stroke
• UniProt ID: EDN3_HUMAN
• PDB ID: 6IGK
• Pfam ID: PF00322
• Sequence:
  MEPGLWLLFGLTVTSAAGFVPCSQSGDAGRRGVSQAPTAARSEGDCEETVAGPGEETVAG
  PGEGTVAPTALQGPSPGSPGQEQAAEGAPEHHRSRRCTCFTYKDKECVYYCHLDIIWINT
  PEQTVPYGLSNYRGSFRGKRSAGPLPGNLQLSHRPHLRCACVGRYDKACLHFCTQTLDVS
  SNSRTAEKTDKEEEGKVEVKDQQSKQALDLHHPKLMPGSGLALAPSTCPRCLFQEGAP
• Function: Endothelins are endothelium-derived vasoconstrictor peptides.
• Tissue Specificity: Expressed in trophoblasts and placental stem villi vessels, but not in cultured placental smooth muscle cells.
• KEGG Pathway:
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Vascular smooth muscle contraction (hsa04270)
  Renin secretion (hsa04924)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Peptide ligand-binding receptors (R-HSA-375276)

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Posttranslational Modification	[2]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[3]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[3]
Bacteremia	DIS6N9RZ	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Posttranslational Modification	[5]
Central hypoventilation syndrome, congenital	DISQRK53	Strong	Biomarker	[6]
Chronic renal failure	DISGG7K6	Strong	Genetic Variation	[4]
Colon cancer	DISVC52G	Strong	Posttranslational Modification	[7]
Colon carcinoma	DISJYKUO	Strong	Posttranslational Modification	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[2]
End-stage renal disease	DISXA7GG	Strong	Genetic Variation	[4]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Haddad syndrome	DISF128S	Strong	Biomarker	[8]
High blood pressure	DISY2OHH	Strong	Biomarker	[9]
HIV infectious disease	DISO97HC	Strong	Biomarker	[10]
Hypotension	DISYNSM9	Strong	Therapeutic	[11]
Interstitial nephritis	DISKQGND	Strong	Altered Expression	[12]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[13]
Neoplasm	DISZKGEW	Strong	Posttranslational Modification	[2]
Waardenburg syndrome	DISRU41A	Strong	Biomarker	[14]
Waardenburg syndrome type 4A	DISSMGSQ	Strong	Genetic Variation	[15]
Waardenburg syndrome type 4B	DISM8SI0	Strong	Autosomal dominant	[16]
Achondroplasia	DISYWN2O	moderate	Biomarker	[17]
Hirschsprung disease	DISUUSM1	moderate	Genetic Variation	[18]
Hirschsprung disease, susceptibility to, 4	DISJC3W2	Moderate	Autosomal dominant	[19]
Waardenburg-Shah syndrome	DISR8C6R	Supportive	Autosomal dominant	[20]
Waardenburg syndrome type 2	DISVZBEV	Disputed	Genetic Variation	[21]
Melanoma	DIS1RRCY	Limited	Altered Expression	[22]
Stroke	DISX6UHX	Limited	Biomarker	[23]

7 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-3 (EDN3).	[24]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Endothelin-3 (EDN3).	[25]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Endothelin-3 (EDN3).	[26]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Endothelin-3 (EDN3).	[27]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea decreases the expression of Endothelin-3 (EDN3).	[28]
ACYLINE	DM9GRTK	Phase 2	ACYLINE decreases the expression of Endothelin-3 (EDN3).	[29]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Endothelin-3 (EDN3).	[31]

1 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 Endothelin-3 (EDN3).	[30]

References

• [1] Autocrine endothelin-3/endothelin receptor B signaling maintains cellular and molecular properties of glioblastoma stem cells.Mol Cancer Res. 2011 Dec;9(12):1668-85. doi: 10.1158/1541-7786.MCR-10-0563. Epub 2011 Oct 19.
• [2] Epigenetic silencing of endothelin-3 in colorectal cancer.Int J Immunopathol Pharmacol. 2016 Jun;29(2):333-40. doi: 10.1177/0394632015600371. Epub 2015 Dec 18.
• [3] SCF-KIT signaling induces endothelin-3 synthesis and secretion: Thereby activates and regulates endothelin-B-receptor for generating temporally- and spatially-precise nitric oxide to modulate SCF- and or KIT-expressing cell functions.PLoS One. 2017 Sep 7;12(9):e0184154. doi: 10.1371/journal.pone.0184154. eCollection 2017.
• [4] Association of endothelin genetic variants and hospitalized infection complications in end-stage renal disease (ESRD) patients.BMC Nephrol. 2019 Jun 5;20(1):203. doi: 10.1186/s12882-019-1349-3.
• [5] Frequent loss of endothelin-3 (EDN3) expression due to epigenetic inactivation in human breast cancer.Breast Cancer Res. 2009;11(3):R34. doi: 10.1186/bcr2319. Epub 2009 Jun 15.
• [6] Endothelin-3 gene mutations in isolated and syndromic Hirschsprung disease.Eur J Hum Genet. 1997 Jul-Aug;5(4):247-51.
• [7] Epigenetic inactivation of endothelin-2 and endothelin-3 in colon cancer.Int J Cancer. 2013 Mar 1;132(5):1004-12. doi: 10.1002/ijc.27762. Epub 2012 Aug 24.
• [8] Endothelin-3 frameshift mutation in congenital central hypoventilation syndrome.Nat Genet. 1996 Aug;13(4):395-6. doi: 10.1038/ng0896-395.
• [9] Effects of endothelin 3 on diastolic blood pressure of pithed Sprague-Dawley, Wistar Kyoto, and spontaneously hypertensive rats before and after pretreatment with nifedipine.Can J Physiol Pharmacol. 1991 Apr;69(4):531-5. doi: 10.1139/y91-080.
• [10] Reconnaissance of the candidate genes involved in the pathogenesis of human immunodeficiency virus and targeted by antiretroviral therapy.J Med Virol. 2019 Dec;91(12):2134-2141. doi: 10.1002/jmv.25549. Epub 2019 Jul 30.
• [11] Central sympathetic control of spinal endothelin release in the rat.Eur J Pharmacol. 1994 Jul 11;259(3):305-8. doi: 10.1016/0014-2999(94)90658-0.
• [12] Primary structure of dog preproendothelin-3 and elevated gene expression in kidney affected with interstitial nephritis.J Cardiovasc Pharmacol. 2004 Nov;44 Suppl 1:S426-9. doi: 10.1097/01.fjc.0000166289.87571.e7.
• [13] Identification of stage-specific biomarkers in lung adenocarcinoma based on RNA-seq data.Tumour Biol. 2015 Aug;36(8):6391-9. doi: 10.1007/s13277-015-3327-0. Epub 2015 Apr 11.
• [14] The clinical and genetic research of Waardenburg syndrome type I and II in Chinese families.Int J Pediatr Otorhinolaryngol. 2020 Mar;130:109806. doi: 10.1016/j.ijporl.2019.109806. Epub 2019 Nov 29.
• [15] Novel mutations in the SOX10 gene in the first two Chinese cases of type IV Waardenburg syndrome.Biochem Biophys Res Commun. 2011 May 20;408(4):620-4. doi: 10.1016/j.bbrc.2011.04.072. Epub 2011 Apr 21.
• [16] Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome). Nat Genet. 1996 Apr;12(4):442-4. doi: 10.1038/ng0496-442.
• [17] Osmotic and non-osmotic regulation of arginine vasopressin (AVP) release, mRNA, and promoter activity in small cell lung carcinoma (SCLC) cells.Mol Cell Endocrinol. 1996 Oct 30;123(2):179-86. doi: 10.1016/s0303-7207(96)03912-3.
• [18] Loss of visceral pain following colorectal distension in an endothelin-3 deficient mouse model of Hirschsprung's disease.J Physiol. 2011 Apr 1;589(Pt 7):1691-706. doi: 10.1113/jphysiol.2010.202820. Epub 2011 Feb 14.
• [19] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [20] Genetic and phenotypic heterogeneity in two novel cases of Waardenburg syndrome type IV. Am J Med Genet A. 2009 Oct;149A(10):2296-302. doi: 10.1002/ajmg.a.33026.
• [21] A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome).Nat Genet. 1996 Apr;12(4):445-7. doi: 10.1038/ng0496-445.
• [22] Endothelin-3 is produced by metastatic melanoma cells and promotes melanoma cell survival.J Cutan Med Surg. 2008 Mar-Apr;12(2):64-70. doi: 10.2310/7750.2008.06164.
• [23] Reduced Hemoglobin Levels Combined with an Increased Plasma Concentration of Vasoconstrictive endothelin-1 are Strongly Associated with Poor Outcome During Acute Ischemic Stroke.Curr Neurovasc Res. 2018;15(3):193-203. doi: 10.2174/1567202615666180726101531.
• [24] 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.
• [25] Application of cDNA microarray to the study of arsenic-induced liver diseases in the population of Guizhou, China. Toxicol Sci. 2001 Jan;59(1):185-92.
• [26] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [27] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [28] Circulating endothelin-3 levels in patients with sickle cell disease during hydroxyurea treatment. Haematologica. 2004 Mar;89(3):360-1.
• [29] Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007 May 15;67(10):5033-41.
• [30] 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.
• [31] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.