Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSZE6L4)

• DOT Name: A disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6)
• Synonyms: ADAM-TS 6; ADAM-TS6; ADAMTS-6; EC 3.4.24.-
• Gene Name: ADAMTS6
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Esophageal squamous cell carcinoma
  Major depressive disorder
  Mood disorder
  Neoplasm
  Osteosarcoma
  Tourette syndrome
• UniProt ID: ATS6_HUMAN
• EC Number: 3.4.24.-
• Pfam ID: PF17771 ; PF19236 ; PF05986 ; PF01562 ; PF08686 ; PF01421 ; PF19030 ; PF00090
• Sequence:
  MEILWKTLTWILSLIMASSEFHSDHRLSYSSQEEFLTYLEHYQLTIPIRVDQNGAFLSFT
  VKNDKHSRRRRSMDPIDPQQAVSKLFFKLSAYGKHFHLNLTLNTDFVSKHFTVEYWGKDG
  PQWKHDFLDNCHYTGYLQDQRSTTKVALSNCVGLHGVIATEDEEYFIEPLKNTTEDSKHF
  SYENGHPHVIYKKSALQQRHLYDHSHCGVSDFTRSGKPWWLNDTSTVSYSLPINNTHIHH
  RQKRSVSIERFVETLVVADKMMVGYHGRKDIEHYILSVMNIVAKLYRDSSLGNVVNIIVA
  RLIVLTEDQPNLEINHHADKSLDSFCKWQKSILSHQSDGNTIPENGIAHHDNAVLITRYD
  ICTYKNKPCGTLGLASVAGMCEPERSCSINEDIGLGSAFTIAHEIGHNFGMNHDGIGNSC
  GTKGHEAAKLMAAHITANTNPFSWSACSRDYITSFLDSGRGTCLDNEPPKRDFLYPAVAP
  GQVYDADEQCRFQYGATSRQCKYGEVCRELWCLSKSNRCVTNSIPAAEGTLCQTGNIEKG
  WCYQGDCVPFGTWPQSIDGGWGPWSLWGECSRTCGGGVSSSLRHCDSPAPSGGGKYCLGE
  RKRYRSCNTDPCPLGSRDFREKQCADFDNMPFRGKYYNWKPYTGGGVKPCALNCLAEGYN
  FYTERAPAVIDGTQCNADSLDICINGECKHVGCDNILGSDAREDRCRVCGGDGSTCDAIE
  GFFNDSLPRGGYMEVVQIPRGSVHIEVREVAMSKNYIALKSEGDDYYINGAWTIDWPRKF
  DVAGTAFHYKRPTDEPESLEALGPTSENLIVMVLLQEQNLGIRYKFNVPITRTGSGDNEV
  GFTWNHQPWSECSATCAGGVQRQEVVCKRLDDNSIVQNNYCDPDSKPPENQRACNTEPCP
  PEWFIGDWLECSKTCDGGMRTRAVLCIRKIGPSEEETLDYSGCLTHRPVEKEPCNNQSCP
  PQWVALDWSECTPKCGPGFKHRIVLCKSSDLSKTFPAAQCPEESKPPVRIRCSLGRCPPP
  RWVTGDWGQCSAQCGLGQQMRTVQCLSYTGQASSDCLETVRPPSMQQCESKCDSTPISNT
  EECKDVNKVAYCPLVLKFKFCSRAYFRQMCCKTCQGH
• Tissue Specificity: Expressed at low levels in placenta and barely detectable in a number of other tissues.
• 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

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[1]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[3]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Osteosarcoma	DISLQ7E2	Limited	Genetic Variation	[4]
Tourette syndrome	DISX9D54	Limited	Unknown	[5]

13 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 6 (ADAMTS6).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6).	[12]
Malathion	DMXZ84M	Approved	Malathion increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6).	[19]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of A disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of A disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6).	[17]

References

• [1] ADAMTS-6 is a predictor of poor prognosis in patients with esophageal squamous cell carcinoma.Exp Mol Pathol. 2018 Apr;104(2):134-139. doi: 10.1016/j.yexmp.2018.02.004. Epub 2018 Feb 21.
• [2] ADAMTS6 suppresses tumor progression via the ERK signaling pathway and serves as a prognostic marker in human breast cancer.Oncotarget. 2016 Sep 20;7(38):61273-61283. doi: 10.18632/oncotarget.11341.
• [3] Analysis of 23andMe antidepressant efficacy survey data: implication of circadian rhythm and neuroplasticity in bupropion response.Transl Psychiatry. 2016 Sep 13;6(9):e889. doi: 10.1038/tp.2016.171.
• [4] 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.
• [5] De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Neuron. 2017 May 3;94(3):486-499.e9. doi: 10.1016/j.neuron.2017.04.024.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [13] 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.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Gene expression and cytosine DNA methylation alterations in induced pluripotent stem-cell-derived human hepatocytes treated with low doses of chemical carcinogens. Arch Toxicol. 2019 Nov;93(11):3335-3344. doi: 10.1007/s00204-019-02569-5. Epub 2019 Sep 25.
• [16] 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.
• [17] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [18] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [19] 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.
• [20] 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.