Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT953SV2)

• DOT Name: A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5)
• Synonyms: ADAM-TS 5; ADAM-TS5; ADAMTS-5; EC 3.4.24.-; A disintegrin and metalloproteinase with thrombospondin motifs 11; ADAM-TS 11; ADAMTS-11; ADMP-2; Aggrecanase-2
• Gene Name: ADAMTS5
• UniProt ID: ATS5_HUMAN
• PDB ID: 2RJQ; 3B8Z; 3HY7; 3HY9; 3HYG; 3LJT; 6YJM
• EC Number: 3.4.24.-
• Pfam ID: PF17771 ; PF19236 ; PF05986 ; PF01421 ; PF19030 ; PF00090
• Sequence:
  MLLGWASLLLCAFRLPLAAVGPAATPAQDKAGQPPTAAAAAQPRRRQGEEVQERAEPPGH
  PHPLAQRRRSKGLVQNIDQLYSGGGKVGYLVYAGGRRFLLDLERDGSVGIAGFVPAGGGT
  SAPWRHRSHCFYRGTVDGSPRSLAVFDLCGGLDGFFAVKHARYTLKPLLRGPWAEEEKGR
  VYGDGSARILHVYTREGFSFEALPPRASCETPASTPEAHEHAPAHSNPSGRAALASQLLD
  QSALSPAGGSGPQTWWRRRRRSISRARQVELLLVADASMARLYGRGLQHYLLTLASIANR
  LYSHASIENHIRLAVVKVVVLGDKDKSLEVSKNAATTLKNFCKWQHQHNQLGDDHEEHYD
  AAILFTREDLCGHHSCDTLGMADVGTICSPERSCAVIEDDGLHAAFTVAHEIGHLLGLSH
  DDSKFCEETFGSTEDKRLMSSILTSIDASKPWSKCTSATITEFLDDGHGNCLLDLPRKQI
  LGPEELPGQTYDATQQCNLTFGPEYSVCPGMDVCARLWCAVVRQGQMVCLTKKLPAVEGT
  PCGKGRICLQGKCVDKTKKKYYSTSSHGNWGSWGSWGQCSRSCGGGVQFAYRHCNNPAPR
  NNGRYCTGKRAIYRSCSLMPCPPNGKSFRHEQCEAKNGYQSDAKGVKTFVEWVPKYAGVL
  PADVCKLTCRAKGTGYYVVFSPKVTDGTECRLYSNSVCVRGKCVRTGCDGIIGSKLQYDK
  CGVCGGDNSSCTKIVGTFNKKSKGYTDVVRIPEGATHIKVRQFKAKDQTRFTAYLALKKK
  NGEYLINGKYMISTSETIIDINGTVMNYSGWSHRDDFLHGMGYSATKEILIVQILATDPT
  KPLDVRYSFFVPKKSTPKVNSVTSHGSNKVGSHTSQPQWVTGPWLACSRTCDTGWHTRTV
  QCQDGNRKLAKGCPLSQRPSAFKQCLLKKC
• Function: Metalloproteinase that plays an important role in connective tissue organization, development, inflammation and cell migration. Extracellular matrix (ECM) degrading enzyme that show proteolytic activity toward the hyalectan group of chondroitin sulfate proteoglycans (CSPGs) including ACAN, VCAN, BCAN and NCAN. Cleavage within the hyalectans occurs at Glu-Xaa recognition motifs. Plays a role in embryonic development, including limb and cardiac morphogenesis, and skeletal muscle development through its VCAN remodeling properties. Cleaves VCAN in the pericellular matrix surrounding myoblasts, facilitating myoblast contact and fusion which is required for skeletal muscle development and regeneration. Participates in development of brown adipose tissue and browning of white adipose tissue. Plays an important role for T-lymphocyte migration from draining lymph nodes following viral infection.
• Tissue Specificity: Expressed at low level in placenta primarily but also detected in heart and brain, cervix, uterus, bladder, esophagus, rib cartilage, chondroblastoma, fibrous tissue and a joint capsule from an arthritic patient.
• 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

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5).	[8]
Selenium	DM25CGV	Approved	Selenium decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5).	[9]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5).	[10]
Glucosamine	DM4ZLFD	Approved	Glucosamine decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5).	[11]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5).	[17]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5).	[15]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] Gamma-irradiation and doxorubicin treatment of normal human cells cause cell cycle arrest via different pathways. Mol Cells. 2005 Dec 31;20(3):331-8.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [7] 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.
• [8] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [9] 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.
• [10] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [11] Glucosamine decreases expression of anabolic and catabolic genes in human osteoarthritic cartilage explants. Osteoarthritis Cartilage. 2006 Mar;14(3):250-7. doi: 10.1016/j.joca.2005.10.001. Epub 2005 Nov 18.
• [12] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [13] 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.
• [14] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [15] 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.
• [16] 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.
• [17] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [18] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.