Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNJ9VSU)

• DOT Name: A disintegrin and metalloproteinase with thrombospondin motifs 10 (ADAMTS10)
• Synonyms: ADAM-TS 10; ADAM-TS10; ADAMTS-10; EC 3.4.24.-
• Gene Name: ADAMTS10
• Related Disease:
  Glaucoma/ocular hypertension
  Weill-Marchesani syndrome 1
  Weill-Marchesani syndrome 2, dominant
  Acromicric dysplasia
  Alzheimer disease
  Major depressive disorder
  Mental disorder
  OPTN-related open angle glaucoma
  Schizophrenia
  Weill-Marchesani 4 syndrome, recessive
  Weill-Marchesani syndrome
  Carpal tunnel syndrome
  Connective tissue disorder
• UniProt ID: ATS10_HUMAN
• EC Number: 3.4.24.-
• Pfam ID: PF17771 ; PF19236 ; PF05986 ; PF01562 ; PF08686 ; PF01421 ; PF19030 ; PF00090
• Sequence:
  MAPACQILRWALALGLGLMFEVTHAFRSQDEFLSSLESYEIAFPTRVDHNGALLAFSPPP
  PRRQRRGTGATAESRLFYKVASPSTHFLLNLTRSSRLLAGHVSVEYWTREGLAWQRAARP
  HCLYAGHLQGQASTSHVAISTCGGLHGLIVADEEEYLIEPLHGGPKGSRSPEESGPHVVY
  KRSSLRHPHLDTACGVRDEKPWKGRPWWLRTLKPPPARPLGNETERGQPGLKRSVSRERY
  VETLVVADKMMVAYHGRRDVEQYVLAIMNIVAKLFQDSSLGSTVNILVTRLILLTEDQPT
  LEITHHAGKSLDSFCKWQKSIVNHSGHGNAIPENGVANHDTAVLITRYDICIYKNKPCGT
  LGLAPVGGMCERERSCSVNEDIGLATAFTIAHEIGHTFGMNHDGVGNSCGARGQDPAKLM
  AAHITMKTNPFVWSSCSRDYITSFLDSGLGLCLNNRPPRQDFVYPTVAPGQAYDADEQCR
  FQHGVKSRQCKYGEVCSELWCLSKSNRCITNSIPAAEGTLCQTHTIDKGWCYKRVCVPFG
  SRPEGVDGAWGPWTPWGDCSRTCGGGVSSSSRHCDSPRPTIGGKYCLGERRRHRSCNTDD
  CPPGSQDFREVQCSEFDSIPFRGKFYKWKTYRGGGVKACSLTCLAEGFNFYTERAAAVVD
  GTPCRPDTVDICVSGECKHVGCDRVLGSDLREDKCRVCGGDGSACETIEGVFSPASPGAG
  YEDVVWIPKGSVHIFIQDLNLSLSHLALKGDQESLLLEGLPGTPQPHRLPLAGTTFQLRQ
  GPDQVQSLEALGPINASLIVMVLARTELPALRYRFNAPIARDSLPPYSWHYAPWTKCSAQ
  CAGGSQVQAVECRNQLDSSAVAPHYCSAHSKLPKRQRACNTEPCPPDWVVGNWSLCSRSC
  DAGVRSRSVVCQRRVSAAEEKALDDSACPQPRPPVLEACHGPTCPPEWAALDWSECTPSC
  GPGLRHRVVLCKSADHRATLPPAHCSPAAKPPATMRCNLRRCPPARWVAGEWGECSAQCG
  VGQRQRSVRCTSHTGQASHECTEALRPPTTQQCEAKCDSPTPGDGPEECKDVNKVAYCPL
  VLKFQFCSRAYFRQMCCKTCHGH
• Function: Metalloprotease that participate in microfibrils assembly. Microfibrils are extracellular matrix components occurring independently or along with elastin in the formation of elastic tissues.
• Tissue Specificity: Widely expressed in adult 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

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glaucoma/ocular hypertension	DISLBXBY	Definitive	Genetic Variation	[1]
Weill-Marchesani syndrome 1	DISX8Q9C	Definitive	Autosomal recessive	[2]
Weill-Marchesani syndrome 2, dominant	DISQUJI6	Definitive	Biomarker	[3]
Acromicric dysplasia	DISMV8M7	Strong	Biomarker	[4]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[6]
Mental disorder	DIS3J5R8	Strong	Biomarker	[7]
OPTN-related open angle glaucoma	DISDR98A	Strong	Biomarker	[1]
Schizophrenia	DISSRV2N	Strong	Biomarker	[8]
Weill-Marchesani 4 syndrome, recessive	DISCL3SY	Strong	Genetic Variation	[9]
Weill-Marchesani syndrome	DIS9B7CX	Supportive	Autosomal dominant	[10]
Carpal tunnel syndrome	DISHQ3BE	Limited	Genetic Variation	[11]
Connective tissue disorder	DISKXBS3	Limited	Genetic Variation	[12]

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 10 (ADAMTS10).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of A disintegrin and metalloproteinase with thrombospondin motifs 10 (ADAMTS10).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 10 (ADAMTS10).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 10 (ADAMTS10).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 10 (ADAMTS10).	[16]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 10 (ADAMTS10).	[17]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 10 (ADAMTS10).	[18]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of A disintegrin and metalloproteinase with thrombospondin motifs 10 (ADAMTS10).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 10 (ADAMTS10).	[21]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 10 (ADAMTS10).	[22]

References

• [1] The microfibril hypothesis of glaucoma: implications for treatment of elevated intraocular pressure.J Ocul Pharmacol Ther. 2014 Mar-Apr;30(2-3):170-80. doi: 10.1089/jop.2013.0184. Epub 2014 Feb 12.
• [2] ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome. Am J Hum Genet. 2004 Nov;75(5):801-6. doi: 10.1086/425231. Epub 2004 Sep 13.
• [3] ADAMTS10-mediated tissue disruption in Weill-Marchesani syndrome.Hum Mol Genet. 2018 Nov 1;27(21):3675-3687. doi: 10.1093/hmg/ddy276.
• [4] Mutations in LTBP3 cause acromicric dysplasia and geleophysic dysplasia. J Med Genet. 2016 Jul;53(7):457-64. doi: 10.1136/jmedgenet-2015-103647. Epub 2016 Apr 11.
• [5] Estrogen regulation of the neprilysin gene through a hormone-responsive element.J Mol Neurosci. 2009 Sep;39(1-2):22-6. doi: 10.1007/s12031-008-9168-1. Epub 2009 Jan 6.
• [6] Clinical and radiological characteristics of early versus late mild cognitive impairment in patients with comorbid depressive disorder.Int J Geriatr Psychiatry. 2018 Dec;33(12):1604-1612. doi: 10.1002/gps.4955. Epub 2018 Jul 23.
• [7] Association of body mass index-related single nucleotide polymorphisms with psychiatric disease and memory performance in a Japanese population.Acta Neuropsychiatr. 2017 Oct;29(5):299-308. doi: 10.1017/neu.2016.66. Epub 2016 Dec 7.
• [8] Subcortical association with memory performance in schizophrenia: a structural magnetic resonance imaging study.Transl Psychiatry. 2018 Jan 10;8(1):20. doi: 10.1038/s41398-017-0069-3.
• [9] 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.
• [10] Weill-Marchesani Syndrome. 2007 Nov 1 [updated 2020 Dec 10]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [11] 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.
• [12] The RECK tumor-suppressor protein binds and stabilizes ADAMTS10.Biol Open. 2018 Oct 4;7(10):bio033985. doi: 10.1242/bio.033985.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [17] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [18] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [19] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [20] 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.
• [21] 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.
• [22] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.