Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL2LSMI)

• DOT Name: Endoglin (ENG)
• Synonyms: CD antigen CD105
• Gene Name: ENG
• Related Disease:
  Telangiectasia, hereditary hemorrhagic, type 1
  Hereditary hemorrhagic telangiectasia
  Juvenile polyposis syndrome
• UniProt ID: EGLN_HUMAN
• PDB ID: 5HZV; 5HZW; 5I04
• Sequence:
  MDRGTLPLAVALLLASCSLSPTSLAETVHCDLQPVGPERGEVTYTTSQVSKGCVAQAPNA
  ILEVHVLFLEFPTGPSQLELTLQASKQNGTWPREVLLVLSVNSSVFLHLQALGIPLHLAY
  NSSLVTFQEPPGVNTTELPSFPKTQILEWAAERGPITSAAELNDPQSILLRLGQAQGSLS
  FCMLEASQDMGRTLEWRPRTPALVRGCHLEGVAGHKEAHILRVLPGHSAGPRTVTVKVEL
  SCAPGDLDAVLILQGPPYVSWLIDANHNMQIWTTGEYSFKIFPEKNIRGFKLPDTPQGLL
  GEARMLNASIVASFVELPLASIVSLHASSCGGRLQTSPAPIQTTPPKDTCSPELLMSLIQ
  TKCADDAMTLVLKKELVAHLKCTITGLTFWDPSCEAEDRGDKFVLRSAYSSCGMQVSASM
  ISNEAVVNILSSSSPQRKKVHCLNMDSLSFQLGLYLSPHFLQASNTIEPGQQSFVQVRVS
  PSVSEFLLQLDSCHLDLGPEGGTVELIQGRAAKGNCVSLLSPSPEGDPRFSFLLHFYTVP
  IPKTGTLSCTVALRPKTGSQDQEVHRTVFMRLNIISPDLSGCTSKGLVLPAVLGITFGAF
  LIGALLTAALWYIYSHTRSPSKREPVVAVAAPASSESSSTNHSIGSTQSTPCSTSSMA
• Function: Vascular endothelium glycoprotein that plays an important role in the regulation of angiogenesis. Required for normal structure and integrity of adult vasculature. Regulates the migration of vascular endothelial cells. Required for normal extraembryonic angiogenesis and for embryonic heart development. May regulate endothelial cell shape changes in response to blood flow, which drive vascular remodeling and establishment of normal vascular morphology during angiogenesis. May play a critical role in the binding of endothelial cells to integrins and/or other RGD receptors. Acts as a TGF-beta coreceptor and is involved in the TGF-beta/BMP signaling cascade that ultimately leads to the activation of SMAD transcription factors. Required for GDF2/BMP9 signaling through SMAD1 in endothelial cells and modulates TGFB1 signaling through SMAD3.
• Tissue Specificity: Detected on umbilical veil endothelial cells . Detected in placenta (at protein level) . Detected on endothelial cells .

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Telangiectasia, hereditary hemorrhagic, type 1	DIS6IJC1	Definitive	Autosomal dominant	[1]
Hereditary hemorrhagic telangiectasia	DISXTDNT	Supportive	Autosomal dominant	[2]
Juvenile polyposis syndrome	DISBPSLH	Limited	Autosomal dominant	[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 Endoglin (ENG).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Endoglin (ENG).	[17]

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 Endoglin (ENG).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Endoglin (ENG).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Endoglin (ENG).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Endoglin (ENG).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Endoglin (ENG).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Endoglin (ENG).	[9]
Selenium	DM25CGV	Approved	Selenium increases the expression of Endoglin (ENG).	[10]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Endoglin (ENG).	[11]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Endoglin (ENG).	[12]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Endoglin (ENG).	[13]
Ximelegatran	DMU8ANS	Approved	Ximelegatran decreases the expression of Endoglin (ENG).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Endoglin (ENG).	[15]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Endoglin (ENG).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Endoglin (ENG).	[18]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Endoglin (ENG).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Endoglin (ENG).	[20]
Erythropoietin	DM3R8YL	Investigative	Erythropoietin increases the expression of Endoglin (ENG).	[21]
CFTRinh-172	DM8TJW3	Investigative	CFTRinh-172 increases the expression of Endoglin (ENG).	[22]

References

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• [2] Hereditary Hemorrhagic Telangiectasia. 2000 Jun 26 [updated 2021 Nov 24]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [3] 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.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [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] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [12] 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.
• [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 Y-27632 on the osteogenic and adipogenic potential of human dental pulp stem cells in vitro. Hum Exp Toxicol. 2022 Jan-Dec;41:9603271221089003. doi: 10.1177/09603271221089003.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1839-44. doi: 10.1073/pnas.1424171112. Epub 2015 Jan 20.
• [17] 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.
• [18] BET protein inhibitor JQ1 inhibits growth and modulates WNT signaling in mesenchymal stem cells. Stem Cell Res Ther. 2016 Feb 1;7:22. doi: 10.1186/s13287-016-0278-3.
• [19] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [20] Bisphenol A-induced epithelial to mesenchymal transition is mediated by cyclooxygenase-2 up-regulation in human endometrial carcinoma cells. Reprod Toxicol. 2015 Dec;58:229-33.
• [21] Raloxifene and n-Acetylcysteine Ameliorate TGF-Signalling in Fibroblasts from Patients with Recessive Dominant Epidermolysis Bullosa. Cells. 2020 Sep 16;9(9):2108. doi: 10.3390/cells9092108.
• [22] CFTR dysfunction increases endoglin and TGF- signaling in airway epithelia. Physiol Rep. 2019 Feb;7(4):e13977. doi: 10.14814/phy2.13977.