Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVKZ1DV)

• DOT Name: A disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS7)
• Synonyms: ADAM-TS 7; ADAM-TS7; ADAMTS-7; EC 3.4.24.-; COMPase
• Gene Name: ADAMTS7
• Related Disease:
  Acute coronary syndrome
  Aortic aneurysm
  Arterial disorder
  Arteriosclerosis
  Arthritis
  Atherosclerosis
  Coronary heart disease
  Hyperlipidemia
  Influenza
  Intervertebral disc degeneration
  Osteoarthritis
  Polycystic ovarian syndrome
  Vascular disease
  Myocardial infarction
  Peripheral arterial disease
  Peripheral vascular disease
  Lung adenocarcinoma
  Lung carcinoma
  Periodontitis
  Rheumatoid arthritis
• UniProt ID: ATS7_HUMAN
• EC Number: 3.4.24.-
• Pfam ID: PF17771 ; PF19236 ; PF05986 ; PF01562 ; PF01421 ; PF19030 ; PF00090
• Sequence:
  MPGGPSPRSPAPLLRPLLLLLCALAPGAPGPAPGRATEGRAALDIVHPVRVDAGGSFLSY
  ELWPRALRKRDVSVRRDAPAFYELQYRGRELRFNLTANQHLLAPGFVSETRRRGGLGRAH
  IRAHTPACHLLGEVQDPELEGGLAAISACDGLKGVFQLSNEDYFIEPLDSAPARPGHAQP
  HVVYKRQAPERLAQRGDSSAPSTCGVQVYPELESRRERWEQRQQWRRPRLRRLHQRSVSK
  EKWVETLVVADAKMVEYHGQPQVESYVLTIMNMVAGLFHDPSIGNPIHITIVRLVLLEDE
  EEDLKITHHADNTLKSFCKWQKSINMKGDAHPLHHDTAILLTRKDLCAAMNRPCETLGLS
  HVAGMCQPHRSCSINEDTGLPLAFTVAHELGHSFGIQHDGSGNDCEPVGKRPFIMSPQLL
  YDAAPLTWSRCSRQYITRFLDRGWGLCLDDPPAKDIIDFPSVPPGVLYDVSHQCRLQYGA
  YSAFCEDMDNVCHTLWCSVGTTCHSKLDAAVDGTRCGENKWCLSGECVPVGFRPEAVDGG
  WSGWSAWSICSRSCGMGVQSAERQCTQPTPKYKGRYCVGERKRFRLCNLQACPAGRPSFR
  HVQCSHFDAMLYKGQLHTWVPVVNDVNPCELHCRPANEYFAEKLRDAVVDGTPCYQVRAS
  RDLCINGICKNVGCDFEIDSGAMEDRCGVCHGNGSTCHTVSGTFEEAEGLGYVDVGLIPA
  GAREIRIQEVAEAANFLALRSEDPEKYFLNGGWTIQWNGDYQVAGTTFTYARRGNWENLT
  SPGPTKEPVWIQLLFQESNPGVHYEYTIHREAGGHDEVPPPVFSWHYGPWTKCTVTCGRG
  VQRQNVYCLERQAGPVDEEHCDPLGRPDDQQRKCSEQPCPARWWAGEWQLCSSSCGPGGL
  SRRAVLCIRSVGLDEQSALEPPACEHLPRPPTETPCNRHVPCPATWAVGNWSQCSVTCGE
  GTQRRNVLCTNDTGVPCDEAQQPASEVTCSLPLCRWPLGTLGPEGSGSGSSSHELFNEAD
  FIPHHLAPRPSPASSPKPGTMGNAIEEEAPELDLPGPVFVDDFYYDYNFINFHEDLSYGP
  SEEPDLDLAGTGDRTPPPHSHPAAPSTGSPVPATEPPAAKEEGVLGPWSPSPWPSQAGRS
  PPPPSEQTPGNPLINFLPEEDTPIGAPDLGLPSLSWPRVSTDGLQTPATPESQNDFPVGK
  DSQSQLPPPWRDRTNEVFKDDEEPKGRGAPHLPPRPSSTLPPLSPVGSTHSSPSPDVAEL
  WTGGTVAWEPALEGGLGPVDSELWPTVGVASLLPPPIAPLPEMKVRDSSLEPGTPSFPTP
  GPGSWDLQTVAVWGTFLPTTLTGLGHMPEPALNPGPKGQPESLSPEVPLSSRLLSTPAWD
  SPANSHRVPETQPLAPSLAEAGPPADPLVVRNAGWQAGNWSECSTTCGLGAVWRPVRCSS
  GRDEDCAPAGRPQPARRCHLRPCATWHSGNWSKCSRSCGGGSSVRDVQCVDTRDLRPLRP
  FHCQPGPAKPPAHRPCGAQPCLSWYTSSWRECSEACGGGEQQRLVTCPEPGLCEEALRPN
  TTRPCNTHPCTQWVVGPWGQCSGPCGGGVQRRLVKCVNTQTGLPEEDSDQCGHEAWPESS
  RPCGTEDCEPVEPPRCERDRLSFGFCETLRLLGRCQLPTIRTQCCRSCSPPSHGAPSRGH
  QRVARR
• Function: Metalloprotease that may play a role in the degradation of COMP.
• Tissue Specificity: Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Detected in meniscus, bone, tendon, cartilage, synovium, fat and ligaments.
• Reactome Pathway:
  O-glycosylation of TSR domain-containing proteins (R-HSA-5173214)
  Defective B3GALTL causes PpS (R-HSA-5083635)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute coronary syndrome	DIS7DYEW	Strong	Genetic Variation	[1]
Aortic aneurysm	DISQ5KRA	Strong	Biomarker	[2]
Arterial disorder	DISLG4XS	Strong	Genetic Variation	[3]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[3]
Arthritis	DIST1YEL	Strong	Biomarker	[4]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[3]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[5]
Hyperlipidemia	DIS61J3S	Strong	Biomarker	[6]
Influenza	DIS3PNU3	Strong	Biomarker	[7]
Intervertebral disc degeneration	DISG3AIM	Strong	Biomarker	[8]
Osteoarthritis	DIS05URM	Strong	Biomarker	[9]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[10]
Vascular disease	DISVS67S	Strong	Biomarker	[2]
Myocardial infarction	DIS655KI	moderate	Biomarker	[11]
Peripheral arterial disease	DIS78WFB	moderate	Genetic Variation	[12]
Peripheral vascular disease	DISXSU1Y	moderate	Genetic Variation	[12]
Lung adenocarcinoma	DISD51WR	Limited	Genetic Variation	[13]
Lung carcinoma	DISTR26C	Limited	Genetic Variation	[13]
Periodontitis	DISI9JOI	Limited	Genetic Variation	[14]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS7).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS7).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS7).	[18]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS7).	[19]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS7).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS7).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS7).	[22]

References

• [1] Association of serum ADAMTS7 levels and genetic variant rs1994016 with acute coronary syndrome in a Chinese population: A case control study.Atherosclerosis. 2018 Aug;275:312-318. doi: 10.1016/j.atherosclerosis.2018.06.872. Epub 2018 Jun 21.
• [2] Upregulation of ADAMTS? and downregulation of COMP are associated with aortic aneurysm.Mol Med Rep. 2017 Oct;16(4):5459-5463. doi: 10.3892/mmr.2017.7293. Epub 2017 Aug 21.
• [3] Association between ADAMTS7 polymorphism and carotid artery plaque vulnerability.Medicine (Baltimore). 2019 Oct;98(43):e17438. doi: 10.1097/MD.0000000000017438.
• [4] Overexpression of ADAMTS-7 leads to accelerated initiation and progression of collagen-induced arthritis in mice.Mol Cell Biochem. 2015 Jun;404(1-2):171-9. doi: 10.1007/s11010-015-2376-4. Epub 2015 Mar 6.
• [5] Identification of Phosphorylation Associated SNPs for Blood Pressure, Coronary Artery Disease and Stroke from Genome-wide Association Studies.Curr Mol Med. 2019;19(10):731-738. doi: 10.2174/1566524019666190828151540.
• [6] Knockout of Adamts7, a novel coronary artery disease locus in humans, reduces atherosclerosis in mice.Circulation. 2015 Mar 31;131(13):1202-1213. doi: 10.1161/CIRCULATIONAHA.114.012669. Epub 2015 Feb 20.
• [7] MicroRNA regulation of human protease genes essential for influenza virus replication.PLoS One. 2012;7(5):e37169. doi: 10.1371/journal.pone.0037169. Epub 2012 May 14.
• [8] IL-17A enhances ADAMTS-7 expression through regulation of TNF- in human nucleus pulposus cells.J Mol Histol. 2015 Dec;46(6):475-83. doi: 10.1007/s10735-015-9640-5. Epub 2015 Oct 7.
• [9] Wnt and RUNX2 mediate cartilage breakdown by osteoarthritis synovial fibroblast-derived ADAMTS-7 and -12.J Cell Mol Med. 2019 Jun;23(6):3974-3983. doi: 10.1111/jcmm.14283. Epub 2019 Mar 22.
• [10] Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
• [11] Proteinases and plaque rupture: unblocking the road to translation.Curr Opin Lipidol. 2014 Oct;25(5):358-66. doi: 10.1097/MOL.0000000000000111.
• [12] Genetic variants rs1994016 and rs3825807 in ADAMTS7 affect its mRNA expression in atherosclerotic occlusive peripheral arterial disease.J Clin Lab Anal. 2018 Jan;32(1):e22174. doi: 10.1002/jcla.22174. Epub 2017 Feb 15.
• [13] Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.Nat Genet. 2017 Jul;49(7):1126-1132. doi: 10.1038/ng.3892. Epub 2017 Jun 12.
• [14] Genome-wide association meta-analysis of coronary artery disease and periodontitis reveals a novel shared risk locus.Sci Rep. 2018 Sep 12;8(1):13678. doi: 10.1038/s41598-018-31980-8.
• [15] ADAMTS-7: a metalloproteinase that directly binds to and degrades cartilage oligomeric matrix protein.FASEB J. 2006 May;20(7):988-90. doi: 10.1096/fj.05-3877fje. Epub 2006 Apr 3.
• [16] 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.
• [17] 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.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [19] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [20] The molecular basis of genistein-induced mitotic arrest and exit of self-renewal in embryonal carcinoma and primary cancer cell lines. BMC Med Genomics. 2008 Oct 10;1:49.
• [21] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [22] 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.