Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2KFY1S)

• DOT Name: A disintegrin and metalloproteinase with thrombospondin motifs 8 (ADAMTS8)
• Synonyms: ADAM-TS 8; ADAM-TS8; ADAMTS-8; EC 3.4.24.-; METH-2; METH-8
• Gene Name: ADAMTS8
• Related Disease:
  Abdominal aortic aneurysm
  Breast cancer
  Breast carcinoma
  Carcinoma
  Colorectal carcinoma
  Dilated cardiomyopathy 1A
  Gastric cancer
  Lung cancer
  Lung carcinoma
  Pancreatic cancer
  Prostate cancer
  Prostate neoplasm
  Pulmonary arterial hypertension
  Stomach cancer
  Keratoconus
  Brain neoplasm
  Glioma
  Neoplasm
  Non-small-cell lung cancer
• UniProt ID: ATS8_HUMAN
• EC Number: 3.4.24.-
• Pfam ID: PF17771 ; PF19236 ; PF05986 ; PF01562 ; PF01421 ; PF19030 ; PF00090
• Sequence:
  MLPAPAAPRWPPLLLLLLLLLPLARGAPARPAAGGQASELVVPTRLPGSAGELALHLSAF
  GKGFVLRLAPDDSFLAPEFKIERLGGSGRATGGERGLRGCFFSGTVNGEPESLAAVSLCR
  GLSGSFLLDGEEFTIQPQGAGGSLAQPHRLQRWGPAGARPLPRGPEWEVETGEGQRQERG
  DHQEDSEEESQEEEAEGASEPPPPLGATSRTKRFVSEARFVETLLVADASMAAFYGADLQ
  NHILTLMSVAARIYKHPSIKNSINLMVVKVLIVEDEKWGPEVSDNGGLTLRNFCNWQRRF
  NQPSDRHPEHYDTAILLTRQNFCGQEGLCDTLGVADIGTICDPNKSCSVIEDEGLQAAHT
  LAHELGHVLSMPHDDSKPCTRLFGPMGKHHVMAPLFVHLNQTLPWSPCSAMYLTELLDGG
  HGDCLLDAPAAALPLPTGLPGRMALYQLDQQCRQIFGPDFRHCPNTSAQDVCAQLWCHTD
  GAEPLCHTKNGSLPWADGTPCGPGHLCSEGSCLPEEEVERPKPVADGGWAPWGPWGECSR
  TCGGGVQFSHRECKDPEPQNGGRYCLGRRAKYQSCHTEECPPDGKSFREQQCEKYNAYNY
  TDMDGNLLQWVPKYAGVSPRDRCKLFCRARGRSEFKVFEAKVIDGTLCGPETLAICVRGQ
  CVKAGCDHVVDSPRKLDKCGVCGGKGNSCRKVSGSLTPTNYGYNDIVTIPAGATNIDVKQ
  RSHPGVQNDGNYLALKTADGQYLLNGNLAISAIEQDILVKGTILKYSGSIATLERLQSFR
  PLPEPLTVQLLTVPGEVFPPKVKYTFFVPNDVDFSMQSSKERATTNIIQPLLHAQWVLGD
  WSECSSTCGAGWQRRTVECRDPSGQASATCNKALKPEDAKPCESQLCPL
• Function: Has anti-angiogenic properties.
• Tissue Specificity: Highly expressed in adult and fetal lung, lower expression in brain, placenta, heart, stomach and fetal brain and kidney.
• Reactome Pathway:
  Defective B3GALTL causes PpS (R-HSA-5083635)
  O-glycosylation of TSR domain-containing proteins (R-HSA-5173214)
  Degradation of the extracellular matrix (R-HSA-1474228)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Abdominal aortic aneurysm	DISD06OF	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Carcinoma	DISH9F1N	Strong	Posttranslational Modification	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[4]
Gastric cancer	DISXGOUK	Strong	Posttranslational Modification	[5]
Lung cancer	DISCM4YA	Strong	Altered Expression	[6]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[6]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[7]
Prostate cancer	DISF190Y	Strong	Biomarker	[8]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[8]
Pulmonary arterial hypertension	DISP8ZX5	Strong	Biomarker	[9]
Stomach cancer	DISKIJSX	Strong	Posttranslational Modification	[5]
Keratoconus	DISOONXH	moderate	Genetic Variation	[10]
Brain neoplasm	DISY3EKS	Disputed	Posttranslational Modification	[11]
Glioma	DIS5RPEH	Disputed	Posttranslational Modification	[11]
Neoplasm	DISZKGEW	Limited	Altered Expression	[3]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 8 (ADAMTS8).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 8 (ADAMTS8).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of A disintegrin and metalloproteinase with thrombospondin motifs 8 (ADAMTS8).	[14]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 8 (ADAMTS8).	[15]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of A disintegrin and metalloproteinase with thrombospondin motifs 8 (ADAMTS8).	[14]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 8 (ADAMTS8).	[16]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 8 (ADAMTS8).	[17]
Rofecoxib	DM3P5DA	Approved	Rofecoxib affects the expression of A disintegrin and metalloproteinase with thrombospondin motifs 8 (ADAMTS8).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 8 (ADAMTS8).	[19]

2 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 A disintegrin and metalloproteinase with thrombospondin motifs 8 (ADAMTS8).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of A disintegrin and metalloproteinase with thrombospondin motifs 8 (ADAMTS8).	[20]

References

• [1] Alterations in phenotype and gene expression of adult human aneurysmal smooth muscle cells by exogenous nitric oxide.Exp Cell Res. 2019 Nov 1;384(1):111589. doi: 10.1016/j.yexcr.2019.111589. Epub 2019 Aug 29.
• [2] ADAMTS8 and ADAMTS15 expression predicts survival in human breast carcinoma.Int J Cancer. 2006 Mar 1;118(5):1241-7. doi: 10.1002/ijc.21476.
• [3] The metalloprotease ADAMTS8 displays antitumor properties through antagonizing EGFR-MEK-ERK signaling and is silenced in carcinomas by CpG methylation.Mol Cancer Res. 2014 Feb;12(2):228-38. doi: 10.1158/1541-7786.MCR-13-0195. Epub 2013 Nov 1.
• [4] Relationship Between ADAMTS8, ADAMTS18, and ADAMTS20 (A Disintegrin and Metalloproteinase with Thrombospondin Motifs) Expressions and Tumor Molecular Classification, Clinical Pathological Parameters, and Prognosis in Breast Invasive Ductal Carcinoma.Med Sci Monit. 2018 Jun 3;24:3726-3735. doi: 10.12659/MSM.907310.
• [5] Downregulation of ADAMTS8 by DNA Hypermethylation in Gastric Cancer and Its Clinical Significance.Biomed Res Int. 2016;2016:5083841. doi: 10.1155/2016/5083841. Epub 2016 Jul 14.
• [6] Clinical verification of plasma messenger RNA as novel noninvasive biomarker identified through bioinformatics analysis for lung cancer.Oncotarget. 2017 Jul 4;8(27):43978-43989. doi: 10.18632/oncotarget.16701.
• [7] Expression of METH-1 and METH-2 in pancreatic cancer.Clin Cancer Res. 2001 Nov;7(11):3437-43.
• [8] The long tail of oncogenic drivers in prostate cancer.Nat Genet. 2018 May;50(5):645-651. doi: 10.1038/s41588-018-0078-z. Epub 2018 Apr 2.
• [9] ADAMTS8 Promotes the Development of Pulmonary Arterial Hypertension and Right Ventricular Failure: A Possible Novel Therapeutic Target.Circ Res. 2019 Oct 25;125(10):884-906. doi: 10.1161/CIRCRESAHA.119.315398. Epub 2019 Sep 26.
• [10] Genetic Variants Associated With Corneal Biomechanical Properties and Potentially Conferring Susceptibility to Keratoconus in a Genome-Wide Association Study.JAMA Ophthalmol. 2019 Sep 1;137(9):1005-1012. doi: 10.1001/jamaophthalmol.2019.2058.
• [11] Expression of ADAMTS-8, a secreted protease with antiangiogenic properties, is downregulated in brain tumours.Br J Cancer. 2006 Apr 24;94(8):1186-93. doi: 10.1038/sj.bjc.6603006.
• [12] 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.
• [13] 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.
• [14] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [15] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [16] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [17] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [18] 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.
• [19] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [20] 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.