Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4CA13K)

• DOT Name: A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4)
• Synonyms: ADAM-TS 4; ADAM-TS4; ADAMTS-4; EC 3.4.24.82; ADMP-1; Aggrecanase-1
• Gene Name: ADAMTS4
• UniProt ID: ATS4_HUMAN
• PDB ID: 2RJP; 3B2Z; 4WK7; 4WKE; 4WKI
• EC Number: 3.4.24.82
• Pfam ID: PF17771 ; PF19236 ; PF05986 ; PF01421 ; PF00090
• Sequence:
  MSQTGSHPGRGLAGRWLWGAQPCLLLPIVPLSWLVWLLLLLLASLLPSARLASPLPREEE
  IVFPEKLNGSVLPGSGAPARLLCRLQAFGETLLLELEQDSGVQVEGLTVQYLGQAPELLG
  GAEPGTYLTGTINGDPESVASLHWDGGALLGVLQYRGAELHLQPLEGGTPNSAGGPGAHI
  LRRKSPASGQGPMCNVKAPLGSPSPRPRRAKRFASLSRFVETLVVADDKMAAFHGAGLKR
  YLLTVMAAAAKAFKHPSIRNPVSLVVTRLVILGSGEEGPQVGPSAAQTLRSFCAWQRGLN
  TPEDSDPDHFDTAILFTRQDLCGVSTCDTLGMADVGTVCDPARSCAIVEDDGLQSAFTAA
  HELGHVFNMLHDNSKPCISLNGPLSTSRHVMAPVMAHVDPEEPWSPCSARFITDFLDNGY
  GHCLLDKPEAPLHLPVTFPGKDYDADRQCQLTFGPDSRHCPQLPPPCAALWCSGHLNGHA
  MCQTKHSPWADGTPCGPAQACMGGRCLHMDQLQDFNIPQAGGWGPWGPWGDCSRTCGGGV
  QFSSRDCTRPVPRNGGKYCEGRRTRFRSCNTEDCPTGSALTFREEQCAAYNHRTDLFKSF
  PGPMDWVPRYTGVAPQDQCKLTCQAQALGYYYVLEPRVVDGTPCSPDSSSVCVQGRCIHA
  GCDRIIGSKKKFDKCMVCGGDGSGCSKQSGSFRKFRYGYNNVVTIPAGATHILVRQQGNP
  GHRSIYLALKLPDGSYALNGEYTLMPSPTDVVLPGAVSLRYSGATAASETLSGHGPLAQP
  LTLQVLVAGNPQDTRLRYSFFVPRPTPSTPRPTPQDWLHRRAQILEILRRRPWAGRK
• Function: Cleaves aggrecan, a cartilage proteoglycan, and may be involved in its turnover. May play an important role in the destruction of aggrecan in arthritic diseases. Could also be a critical factor in the exacerbation of neurodegeneration in Alzheimer disease. Cleaves aggrecan at the '392-Glu-|-Ala-393' site.
• Tissue Specificity: Expressed in brain, lung and heart . Expressed at very low level in placenta and skeletal muscles . Isoform 2: Detected in osteoarthritic synovium .
• 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)
• BioCyc Pathway: MetaCyc:ENSG00000158859-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 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 4 (ADAMTS4).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4).	[10]

11 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 4 (ADAMTS4).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4).	[5]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4).	[6]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4).	[8]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4).	[9]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4).	[11]
WIN-55212-2	DMACBIW	Terminated	WIN-55212-2 decreases the activity of A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4).	[13]

References

• [1] 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.
• [2] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [3] 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.
• [4] 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.
• [5] Research resource: STR DNA profile and gene expression comparisons of human BG-1 cells and a BG-1/MCF-7 clonal variant. Mol Endocrinol. 2014 Dec;28(12):2072-81.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [7] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Comparison between chondroprotective effects of glucosamine, curcumin, and diacerein in IL-1beta-stimulated C-28/I2 chondrocytes. Osteoarthritis Cartilage. 2008 Oct;16(10):1205-12. doi: 10.1016/j.joca.2008.01.013. Epub 2008 Mar 5.
• [10] 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.
• [11] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [12] Cannabinoid WIN?55,212?2 mesylate inhibits ADAMTS?4 activity in human osteoarthritic articular chondrocytes by inhibiting expression of syndecan?1. Mol Med Rep. 2016 Jun;13(6):4569-76. doi: 10.3892/mmr.2016.5137. Epub 2016 Apr 15.
• [13] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.