Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCFITM9)

• DOT Name: A disintegrin and metalloproteinase with thrombospondin motifs 17 (ADAMTS17)
• Synonyms: ADAM-TS 17; ADAM-TS17; ADAMTS-17; EC 3.4.24.-
• Gene Name: ADAMTS17
• Related Disease:
  Disorder of orbital region
  OPTN-related open angle glaucoma
  Weill-Marchesani 4 syndrome, recessive
  Breast cancer
  Breast carcinoma
  Ductal carcinoma
  Gastroesophageal reflux disease
  Isolated ectopia lentis
  Liver cancer
  Weill-Marchesani syndrome
  Keratoconus
  Carpal tunnel syndrome
  Geleophysic dysplasia
  Osteosarcoma
• UniProt ID: ATS17_HUMAN
• EC Number: 3.4.24.-
• Pfam ID: PF17771 ; PF19236 ; PF05986 ; PF01562 ; PF01421 ; PF19030 ; PF00090
• Sequence:
  MCDGALLPPLVLPVLLLLVWGLDPGTAVGDAAADVEVVLPWRVRPDDVHLPPLPAAPGPR
  RRRRPRTPPAAPRARPGERALLLHLPAFGRDLYLQLRRDLRFLSRGFEVEEAGAARRRGR
  PAELCFYSGRVLGHPGSLVSLSACGAAGGLVGLIQLGQEQVLIQPLNNSQGPFSGREHLI
  RRKWSLTPSPSAEAQRPEQLCKVLTEKKKPTWGRPSRDWRERRNAIRLTSEHTVETLVVA
  DADMVQYHGAEAAQRFILTVMNMVYNMFQHQSLGIKINIQVTKLVLLRQRPAKLSIGHHG
  ERSLESFCHWQNEEYGGARYLGNNQVPGGKDDPPLVDAAVFVTRTDFCVHKDEPCDTVGI
  AYLGGVCSAKRKCVLAEDNGLNLAFTIAHELGHNLGMNHDDDHSSCAGRSHIMSGEWVKG
  RNPSDLSWSSCSRDDLENFLKSKVSTCLLVTDPRSQHTVRLPHKLPGMHYSANEQCQILF
  GMNATFCRNMEHLMCAGLWCLVEGDTSCKTKLDPPLDGTECGADKWCRAGECVSKTPIPE
  HVDGDWSPWGAWSMCSRTCGTGARFRQRKCDNPPPGPGGTHCPGASVEHAVCENLPCPKG
  LPSFRDQQCQAHDRLSPKKKGLLTAVVVDDKPCELYCSPLGKESPLLVADRVLDGTPCGP
  YETDLCVHGKCQKIGCDGIIGSAAKEDRCGVCSGDGKTCHLVKGDFSHARGTALKDSGKG
  SINSDWKIELPGEFQIAGTTVRYVRRGLWEKISAKGPTKLPLHLMVLLFHDQDYGIHYEY
  TVPVNRTAENQSEPEKPQDSLFIWTHSGWEGCSVQCGGGERRTIVSCTRIVNKTTTLVND
  SDCPQASRPEPQVRRCNLHPCQSRWVAGPWSPCSATCEKGFQHREVTCVYQLQNGTHVAT
  RPLYCPGPRPAAVQSCEGQDCLSIWEASEWSQCSASCGKGVWKRTVACTNSQGKCDASTR
  PRAEEACEDYSGCYEWKTGDWSTCSSTCGKGLQSRVVQCMHKVTGRHGSECPALSKPAPY
  RQCYQEVCNDRINANTITSPRLAALTYKCTRDQWTVYCRVIREKNLCQDMRWYQRCCQTC
  RDFYANKMRQPPPNS
• Tissue Specificity: Isoform 1 and isoform 2 are expressed at high levels in the lung, brain, whole eye and retina. Isoform 1 shows a weaker expression in the heart, kidney and skeletal muscle. Isoform 2 shows a weaker expression in the kidney, bone marrow and skeletal muscle. Isoform 1 and isoform 2 are expressed at high levels in the fetal heart, kidney, and whole eye, whereas a weak expression is seen in the fetal liver.
• 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

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Disorder of orbital region	DISH0ECJ	Definitive	Genetic Variation	[1]
OPTN-related open angle glaucoma	DISDR98A	Definitive	Genetic Variation	[1]
Weill-Marchesani 4 syndrome, recessive	DISCL3SY	Definitive	Autosomal recessive	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Ductal carcinoma	DIS15EA5	Strong	Altered Expression	[3]
Gastroesophageal reflux disease	DISQ8G5S	Strong	Genetic Variation	[4]
Isolated ectopia lentis	DISJWTN6	Strong	Biomarker	[5]
Liver cancer	DISDE4BI	Strong	Biomarker	[6]
Weill-Marchesani syndrome	DIS9B7CX	Strong	Genetic Variation	[7]
Keratoconus	DISOONXH	moderate	Genetic Variation	[8]
Carpal tunnel syndrome	DISHQ3BE	Limited	Genetic Variation	[9]
Geleophysic dysplasia	DISZOO1G	Limited	Biomarker	[10]
Osteosarcoma	DISLQ7E2	Limited	Genetic Variation	[11]

3 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 A disintegrin and metalloproteinase with thrombospondin motifs 17 (ADAMTS17).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of A disintegrin and metalloproteinase with thrombospondin motifs 17 (ADAMTS17).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of A disintegrin and metalloproteinase with thrombospondin motifs 17 (ADAMTS17).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 17 (ADAMTS17).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 17 (ADAMTS17).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 17 (ADAMTS17).	[15]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 17 (ADAMTS17).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 17 (ADAMTS17).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 17 (ADAMTS17).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 17 (ADAMTS17).	[20]

References

• [1] Unusual life cycle and impact on microfibril assembly of ADAMTS17, a secreted metalloprotease mutated in genetic eye disease.Sci Rep. 2017 Feb 8;7:41871. doi: 10.1038/srep41871.
• [2] Whole exome sequencing identifies a novel splice-site mutation in ADAMTS17 in an Indian family with Weill-Marchesani syndrome. Mol Vis. 2014 Jun 12;20:790-6. eCollection 2014.
• [3] Sp1 is necessary for gene activation of Adamts17 by estrogen.J Cell Biochem. 2014 Oct;115(10):1829-39. doi: 10.1002/jcb.24855.
• [4] Polymorphisms of the BARX1 and ADAMTS17 Locus Genes in Individuals With Gastroesophageal Reflux Disease.J Neurogastroenterol Motil. 2019 Jul 1;25(3):436-441. doi: 10.5056/jnm18183.
• [5] ADAMTS proteins as modulators of microfibril formation and function.Matrix Biol. 2015 Sep;47:34-43. doi: 10.1016/j.matbio.2015.05.004. Epub 2015 May 7.
• [6] Multiple genes exhibit phenobarbital-induced constitutive active/androstane receptor-mediated DNA methylation changes during liver tumorigenesis and in liver tumors.Toxicol Sci. 2009 Apr;108(2):273-89. doi: 10.1093/toxsci/kfp031. Epub 2009 Feb 20.
• [7] A novel nonsense mutation in ADAMTS17 caused autosomal recessive inheritance Weill-Marchesani syndrome from a Chinese family.J Hum Genet. 2019 Jul;64(7):681-687. doi: 10.1038/s10038-019-0608-2. Epub 2019 Apr 25.
• [8] 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.
• [9] A genome-wide association analysis identifies 16 novel susceptibility loci for carpal tunnel syndrome.Nat Commun. 2019 Mar 4;10(1):1030. doi: 10.1038/s41467-019-08993-6.
• [10] Genetic and functional linkage between ADAMTS superfamily proteins and fibrillin-1: a novel mechanism influencing microfibril assembly and function.Cell Mol Life Sci. 2011 Oct;68(19):3137-48. doi: 10.1007/s00018-011-0780-9. Epub 2011 Aug 20.
• [11] Genome-wide association study identifies two susceptibility loci for osteosarcoma.Nat Genet. 2013 Jul;45(7):799-803. doi: 10.1038/ng.2645. Epub 2013 Jun 2.
• [12] 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.
• [13] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [14] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [15] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [16] 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.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] 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.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.