Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPFHC6F)

• DOT Name: Endothelin-converting enzyme 1 (ECE1)
• Synonyms: ECE-1; EC 3.4.24.71
• Gene Name: ECE1
• Related Disease: Essential hypertension, genetic
• UniProt ID: ECE1_HUMAN
• PDB ID: 3DWB
• EC Number: 3.4.24.71
• Pfam ID: PF01431 ; PF05649
• Sequence:
  MRGVWPPPVSALLSALGMSTYKRATLDEEDLVDSLSEGDAYPNGLQVNFHSPRSGQRCWA
  ARTQVEKRLVVLVVLLAAGLVACLAALGIQYQTRSPSVCLSEACVSVTSSILSSMDPTVD
  PCHDFFSYACGGWIKANPVPDGHSRWGTFSNLWEHNQAIIKHLLENSTASVSEAERKAQV
  YYRACMNETRIEELRAKPLMELIERLGGWNITGPWAKDNFQDTLQVVTAHYRTSPFFSVY
  VSADSKNSNSNVIQVDQSGLGLPSRDYYLNKTENEKVLTGYLNYMVQLGKLLGGGDEEAI
  RPQMQQILDFETALANITIPQEKRRDEELIYHKVTAAELQTLAPAINWLPFLNTIFYPVE
  INESEPIVVYDKEYLEQISTLINTTDRCLLNNYMIWNLVRKTSSFLDQRFQDADEKFMEV
  MYGTKKTCLPRWKFCVSDTENNLGFALGPMFVKATFAEDSKSIATEIILEIKKAFEESLS
  TLKWMDEETRKSAKEKADAIYNMIGYPNFIMDPKELDKVFNDYTAVPDLYFENAMRFFNF
  SWRVTADQLRKAPNRDQWSMTPPMVNAYYSPTKNEIVFPAGILQAPFYTRSSPKALNFGG
  IGVVVGHELTHAFDDQGREYDKDGNLRPWWKNSSVEAFKRQTECMVEQYSNYSVNGEPVN
  GRHTLGENIADNGGLKAAYRAYQNWVKKNGAEHSLPTLGLTNNQLFFLGFAQVWCSVRTP
  ESSHEGLITDPHSPSRFRVIGSLSNSKEFSEHFRCPPGSPMNPPHKCEVW
• Function: Converts big endothelin-1 to endothelin-1.
• Tissue Specificity: All isoforms are expressed in umbilical vein endothelial cells, polynuclear neutrophils, fibroblasts, atrium cardiomyocytes and ventricles. Isoforms A, B and C are also expressed in placenta, lung, heart, adrenal gland and phaeochromocytoma; isoforms A and C in liver, testis and small intestine; isoform B, C and D in endothelial cells and umbilical vein smooth muscle cells; isoforms C and D in saphenous vein cells, and isoform C in kidney.
• Reactome Pathway: 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
Essential hypertension, genetic	DISIVD4P	No Known	Unknown	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Endothelin-converting enzyme 1 (ECE1).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Endothelin-converting enzyme 1 (ECE1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Endothelin-converting enzyme 1 (ECE1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Endothelin-converting enzyme 1 (ECE1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Endothelin-converting enzyme 1 (ECE1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Endothelin-converting enzyme 1 (ECE1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Endothelin-converting enzyme 1 (ECE1).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Endothelin-converting enzyme 1 (ECE1).	[8]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Endothelin-converting enzyme 1 (ECE1).	[9]
Acocantherin	DM7JT24	Approved	Acocantherin increases the expression of Endothelin-converting enzyme 1 (ECE1).	[10]
Metoprolol	DMOJ0V6	Approved	Metoprolol decreases the expression of Endothelin-converting enzyme 1 (ECE1).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Endothelin-converting enzyme 1 (ECE1).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Endothelin-converting enzyme 1 (ECE1).	[13]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Endothelin-converting enzyme 1 (ECE1).	[14]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Endothelin-converting enzyme 1 (ECE1).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Endothelin-converting enzyme 1 (ECE1).	[17]
Zibotentan	DMIK6C9	Discontinued in Phase 3	Zibotentan decreases the expression of Endothelin-converting enzyme 1 (ECE1).	[6]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Endothelin-converting enzyme 1 (ECE1).	[18]
CGS-26303	DMFZM09	Terminated	CGS-26303 decreases the activity of Endothelin-converting enzyme 1 (ECE1).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Endothelin-converting enzyme 1 (ECE1).	[20]

References

• [1] Differential binding of transcription factor E2F-2 to the endothelin-converting enzyme-1b promoter affects blood pressure regulation. Hum Mol Genet. 2003 Feb 15;12(4):423-33. doi: 10.1093/hmg/ddg040.
• [2] 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.
• [3] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] 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.
• [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] 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.
• [8] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [9] Cannabidiol Modulates the Expression of Alzheimer's Disease-Related Genes in Mesenchymal Stem Cells. Int J Mol Sci. 2016 Dec 23;18(1):26. doi: 10.3390/ijms18010026.
• [10] Proteomics investigation of protein expression changes in ouabain induced apoptosis in human umbilical vein endothelial cells. J Cell Biochem. 2008 Jun 1;104(3):1054-64. doi: 10.1002/jcb.21691.
• [11] Endothelin converting-enzyme-1 mRNA expression in human cardiovascular disease. Clin Exp Hypertens. 1998 May;20(4):417-37. doi: 10.3109/10641969809053222.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] Structure-activity relationship of resveratrol and its analogue, 4,4'-dihydroxy-trans-stilbene, toward the endothelin axis in human endothelial cells. J Med Food. 2011 Oct;14(10):1173-80. doi: 10.1089/jmf.2010.0272. Epub 2011 May 9.
• [15] Genistein affects the expression of genes involved in blood pressure regulation and angiogenesis in primary human endothelial cells. Nutr Metab Cardiovasc Dis. 2006 Jan;16(1):35-43. doi: 10.1016/j.numecd.2005.03.003. Epub 2005 Jul 28.
• [16] 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.
• [17] 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.
• [18] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [19] Potent and selective non-peptidic inhibitors of endothelin-converting enzyme-1 with sustained duration of action. J Med Chem. 2000 Feb 10;43(3):488-504. doi: 10.1021/jm990507o.
• [20] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.