Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYB6JS3)

• DOT Name: A disintegrin and metalloproteinase with thrombospondin motifs 15 (ADAMTS15)
• Synonyms: ADAM-TS 15; ADAM-TS15; ADAMTS-15; EC 3.4.24.-
• Gene Name: ADAMTS15
• Related Disease:
  Advanced cancer
  Breast carcinoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Leiomyoma
  Neoplasm
  Osteoarthritis
  Prostate neoplasm
  Uterine fibroids
  Gastric cancer
  Stomach cancer
• UniProt ID: ATS15_HUMAN
• EC Number: 3.4.24.-
• Pfam ID: PF17771 ; PF19236 ; PF05986 ; PF01562 ; PF01421 ; PF19030 ; PF00090
• Sequence:
  MLLLGILTLAFAGRTAGGSEPEREVVVPIRLDPDINGRRYYWRGPEDSGDQGLIFQITAF
  QEDFYLHLTPDAQFLAPAFSTEHLGVPLQGLTGGSSDLRRCFYSGDVNAEPDSFAAVSLC
  GGLRGAFGYRGAEYVISPLPNASAPAAQRNSQGAHLLQRRGVPGGPSGDPTSRCGVASGW
  NPAILRALDPYKPRRAGFGESRSRRRSGRAKRFVSIPRYVETLVVADESMVKFHGADLEH
  YLLTLLATAARLYRHPSILNPINIVVVKVLLLRDRDSGPKVTGNAALTLRNFCAWQKKLN
  KVSDKHPEYWDTAILFTRQDLCGATTCDTLGMADVGTMCDPKRSCSVIEDDGLPSAFTTA
  HELGHVFNMPHDNVKVCEEVFGKLRANHMMSPTLIQIDRANPWSACSAAIITDFLDSGHG
  DCLLDQPSKPISLPEDLPGASYTLSQQCELAFGVGSKPCPYMQYCTKLWCTGKAKGQMVC
  QTRHFPWADGTSCGEGKLCLKGACVERHNLNKHRVDGSWAKWDPYGPCSRTCGGGVQLAR
  RQCTNPTPANGGKYCEGVRVKYRSCNLEPCPSSASGKSFREEQCEAFNGYNHSTNRLTLA
  VAWVPKYSGVSPRDKCKLICRANGTGYFYVLAPKVVDGTLCSPDSTSVCVQGKCIKAGCD
  GNLGSKKRFDKCGVCGGDNKSCKKVTGLFTKPMHGYNFVVAIPAGASSIDIRQRGYKGLI
  GDDNYLALKNSQGKYLLNGHFVVSAVERDLVVKGSLLRYSGTGTAVESLQASRPILEPLT
  VEVLSVGKMTPPRVRYSFYLPKEPREDKSSHPKDPRGPSVLHNSVLSLSNQVEQPDDRPP
  ARWVAGSWGPCSASCGSGLQKRAVDCRGSAGQRTVPACDAAHRPVETQACGEPCPTWELS
  AWSPCSKSCGRGFQRRSLKCVGHGGRLLARDQCNLHRKPQELDFCVLRPC
• Function: Metalloprotease which has proteolytic activity against the proteoglycan VCAN, cleaving it at the 'Glu-1428-|-1429-Ala' site. Cleaves VCAN in the pericellular matrix surrounding myoblasts, facilitating myoblast contact and fusion which is required for skeletal muscle development and regeneration.
• Tissue Specificity: Expressed in fetal liver and kidney, but not in any of the adult tissues examined.
• 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

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[1]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Leiomyoma	DISLDDFN	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[1]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[5]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[6]
Uterine fibroids	DISBZRMJ	Strong	Altered Expression	[4]
Gastric cancer	DISXGOUK	Disputed	Biomarker	[7]
Stomach cancer	DISKIJSX	Disputed	Biomarker	[7]

11 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 15 (ADAMTS15).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 15 (ADAMTS15).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 15 (ADAMTS15).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 15 (ADAMTS15).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 15 (ADAMTS15).	[13]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 15 (ADAMTS15).	[13]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 15 (ADAMTS15).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 15 (ADAMTS15).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 15 (ADAMTS15).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 15 (ADAMTS15).	[13]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 15 (ADAMTS15).	[18]

2 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 15 (ADAMTS15).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of A disintegrin and metalloproteinase with thrombospondin motifs 15 (ADAMTS15).	[15]

References

• [1] Genetic inactivation of ADAMTS15 metalloprotease in human colorectal cancer.Cancer Res. 2009 Jun 1;69(11):4926-34. doi: 10.1158/0008-5472.CAN-08-4155. Epub 2009 May 19.
• [2] ADAMTS8 and ADAMTS15 expression predicts survival in human breast carcinoma.Int J Cancer. 2006 Mar 1;118(5):1241-7. doi: 10.1002/ijc.21476.
• [3] Protective roles of matrix metalloproteinases: from mouse models to human cancer.Cell Cycle. 2009 Nov 15;8(22):3657-62. doi: 10.4161/cc.8.22.9956. Epub 2009 Dec 1.
• [4] Versican Proteolysis by ADAMTS Proteases and Its Influence on Sex Steroid Receptor Expression in Uterine Leiomyoma.J Clin Endocrinol Metab. 2017 May 1;102(5):1631-1641. doi: 10.1210/jc.2016-3527.
• [5] Expression profiling of metalloproteinases and their inhibitors in cartilage.Arthritis Rheum. 2004 Jan;50(1):131-41. doi: 10.1002/art.11433.
• [6] The expression and regulation of ADAMTS-1, -4, -5, -9, and -15, and TIMP-3 by TGFbeta1 in prostate cells: relevance to the accumulation of versican.Prostate. 2005 May 15;63(3):269-75. doi: 10.1002/pros.20182.
• [7] A targeted proteomics approach reveals a serum protein signature as diagnostic biomarker for resectable gastric cancer.EBioMedicine. 2019 Jun;44:322-333. doi: 10.1016/j.ebiom.2019.05.044. Epub 2019 May 28.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] Profile of estrogen-responsive genes in an estrogen-specific mammary gland outgrowth model. Mol Reprod Dev. 2009 Aug;76(8):733-50. doi: 10.1002/mrd.21041.
• [11] 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.
• [12] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [13] 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.
• [14] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [15] 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.
• [16] 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.
• [17] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [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.