Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG7HEA2)

• DOT Name: A disintegrin and metalloproteinase with thrombospondin motifs 12 (ADAMTS12)
• Synonyms: ADAM-TS 12; ADAM-TS12; ADAMTS-12; EC 3.4.24.-
• Gene Name: ADAMTS12
• Related Disease:
  Advanced cancer
  Arthritis
  Brachydactyly
  Colon cancer
  Colon carcinoma
  Esophageal squamous cell carcinoma
  Immunodeficiency
  Lung carcinoma
  Osteoarthritis
  Rheumatoid arthritis
  Schizophrenia
  Asthma
  Colorectal carcinoma
  Breast cancer
  Breast carcinoma
  Neoplasm
• UniProt ID: ATS12_HUMAN
• EC Number: 3.4.24.-
• Pfam ID: PF17771 ; PF19236 ; PF05986 ; PF01562 ; PF01421 ; PF19030 ; PF00090
• Sequence:
  MPCAQRSWLANLSVVAQLLNFGALCYGRQPQPGPVRFPDRRQEHFIKGLPEYHVVGPVRV
  DASGHFLSYGLHYPITSSRRKRDLDGSEDWVYYRISHEEKDLFFNLTVNQGFLSNSYIME
  KRYGNLSHVKMMASSAPLCHLSGTVLQQGTRVGTAALSACHGLTGFFQLPHGDFFIEPVK
  KHPLVEGGYHPHIVYRRQKVPETKEPTCGLKDSVNISQKQELWREKWERHNLPSRSLSRR
  SISKERWVETLVVADTKMIEYHGSENVESYILTIMNMVTGLFHNPSIGNAIHIVVVRLIL
  LEEEEQGLKIVHHAEKTLSSFCKWQKSINPKSDLNPVHHDVAVLLTRKDICAGFNRPCET
  LGLSHLSGMCQPHRSCNINEDSGLPLAFTIAHELGHSFGIQHDGKENDCEPVGRHPYIMS
  RQLQYDPTPLTWSKCSEEYITRFLDRGWGFCLDDIPKKKGLKSKVIAPGVIYDVHHQCQL
  QYGPNATFCQEVENVCQTLWCSVKGFCRSKLDAAADGTQCGEKKWCMAGKCITVGKKPES
  IPGGWGRWSPWSHCSRTCGAGVQSAERLCNNPEPKFGGKYCTGERKRYRLCNVHPCRSEA
  PTFRQMQCSEFDTVPYKNELYHWFPIFNPAHPCELYCRPIDGQFSEKMLDAVIDGTPCFE
  GGNSRNVCINGICKMVGCDYEIDSNATEDRCGVCLGDGSSCQTVRKMFKQKEGSGYVDIG
  LIPKGARDIRVMEIEGAGNFLAIRSEDPEKYYLNGGFIIQWNGNYKLAGTVFQYDRKGDL
  EKLMATGPTNESVWIQLLFQVTNPGIKYEYTIQKDGLDNDVEQQMYFWQYGHWTECSVTC
  GTGIRRQTAHCIKKGRGMVKATFCDPETQPNGRQKKCHEKACPPRWWAGEWEACSATCGP
  HGEKKRTVLCIQTMVSDEQALPPTDCQHLLKPKTLLSCNRDILCPSDWTVGNWSECSVSC
  GGGVRIRSVTCAKNHDEPCDVTRKPNSRALCGLQQCPSSRRVLKPNKGTISNGKNPPTLK
  PVPPPTSRPRMLTTPTGPESMSTSTPAISSPSPTTASKEGDLGGKQWQDSSTQPELSSRY
  LISTGSTSQPILTSQSLSIQPSEENVSSSDTGPTSEGGLVATTTSGSGLSSSRNPITWPV
  TPFYNTLTKGPEMEIHSGSGEEREQPEDKDESNPVIWTKIRVPGNDAPVESTEMPLAPPL
  TPDLSRESWWPPFSTVMEGLLPSQRPTTSETGTPRVEGMVTEKPANTLLPLGGDHQPEPS
  GKTANRNHLKLPNNMNQTKSSEPVLTEEDATSLITEGFLLNASNYKQLTNGHGSAHWIVG
  NWSECSTTCGLGAYWRRVECSTQMDSDCAAIQRPDPAKRCHLRPCAGWKVGNWSKCSRNC
  SGGFKIREIQCVDSRDHRNLRPFHCQFLAGIPPPLSMSCNPEPCEAWQVEPWSQCSRSCG
  GGVQERGVFCPGGLCDWTKRPTSTMSCNEHLCCHWATGNWDLCSTSCGGGFQKRTVQCVP
  SEGNKTEDQDQCLCDHKPRPPEFKKCNQQACKKSADLLCTKDKLSASFCQTLKAMKKCSV
  PTVRAECCFSCPQTHITHTQRQRRQRLLQKSKEL
• Function: Metalloprotease that may play a role in the degradation of COMP. Cleaves also alpha-2 macroglobulin and aggregan. Has anti-tumorigenic properties.
• Tissue Specificity: Expressed in skeletal muscle and fat.
• 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

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Posttranslational Modification	[1]
Arthritis	DIST1YEL	Strong	Biomarker	[2]
Brachydactyly	DIS2533F	Strong	Genetic Variation	[3]
Colon cancer	DISVC52G	Strong	Altered Expression	[1]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[1]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[4]
Immunodeficiency	DIS093I0	Strong	Biomarker	[1]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[1]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[5]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[2]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[6]
Asthma	DISW9QNS	moderate	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	moderate	Posttranslational Modification	[8]
Breast cancer	DIS7DPX1	Limited	Biomarker	[9]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[9]
Neoplasm	DISZKGEW	Limited	Altered Expression	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 12 (ADAMTS12).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 12 (ADAMTS12).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 12 (ADAMTS12).	[12]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 12 (ADAMTS12).	[13]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 12 (ADAMTS12).	[14]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 12 (ADAMTS12).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 12 (ADAMTS12).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 12 (ADAMTS12).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of A disintegrin and metalloproteinase with thrombospondin motifs 12 (ADAMTS12).	[18]

References

• [1] The ADAMTS12 metalloprotease gene is epigenetically silenced in tumor cells and transcriptionally activated in the stroma during progression of colon cancer.J Cell Sci. 2009 Aug 15;122(Pt 16):2906-13. doi: 10.1242/jcs.050468. Epub 2009 Jul 28.
• [2] Role of ADAMTS-12 in Protecting Against Inflammatory Arthritis in Mice By Interacting With and Inactivating Proinflammatory Connective Tissue Growth Factor.Arthritis Rheumatol. 2018 Nov;70(11):1745-1756. doi: 10.1002/art.40552. Epub 2018 Sep 24.
• [3] Co-segregation of Freiberg's infraction with a familial translocation t(5;7)(p13.3;p22.2) ascertained by a child with cri du chat syndrome and brachydactyly type A1B.Am J Med Genet A. 2015 Feb;167A(2):445-9. doi: 10.1002/ajmg.a.36874.
• [4] Comprehensive bioinformatics analysis identifies lncRNA HCG22 as a migration inhibitor in esophageal squamous cell carcinoma.J Cell Biochem. 2020 Jan;121(1):468-481. doi: 10.1002/jcb.29218. Epub 2019 Jun 25.
• [5] 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.
• [6] Genetic variations in the ADAMTS12 gene are associated with schizophrenia in Puerto Rican patients of Spanish descent.Neuromolecular Med. 2012 Mar;14(1):53-64. doi: 10.1007/s12017-012-8169-y. Epub 2012 Feb 10.
• [7] Control of allergen-induced inflammation and hyperresponsiveness by the metalloproteinase ADAMTS-12.J Immunol. 2012 Oct 15;189(8):4135-43. doi: 10.4049/jimmunol.1103739. Epub 2012 Sep 7.
• [8] Long non-coding RNA AK001058 regulates tumor growth and angiogenesis in colorectal cancer via methylation of ADAMTS12.Am J Transl Res. 2019 Sep 15;11(9):6117-6123. eCollection 2019.
• [9] Interaction between the ADAMTS-12 metalloprotease and fibulin-2 induces tumor-suppressive effects in breast cancer cells.Oncotarget. 2014 Mar 15;5(5):1253-64. doi: 10.18632/oncotarget.1690.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] 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.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [15] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [16] 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.
• [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] 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.