Details of Drug Off-Target (DOT)

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

• DOT Name: Thrombospondin-3 (THBS3)
• Gene Name: THBS3
• Related Disease:
  Attention deficit hyperactivity disorder
  Bone osteosarcoma
  Gaucher disease
  Mood disorder
  Osteosarcoma
  Stomach cancer
  Cardiomyopathy
  Tourette syndrome
• UniProt ID: TSP3_HUMAN
• Pfam ID: PF11598 ; PF07645 ; PF02412 ; PF05735
• Sequence:
  METQELRGALALLLLCFFTSASQDLQVIDLLTVGESRQMVAVAEKIRTALLTAGDIYLLS
  TFRLPPKQGGVLFGLYSRQDNTRWLEASVVGKINKVLVRYQREDGKVHAVNLQQAGLADG
  RTHTVLLRLRGPSRPSPALHLYVDCKLGDQHAGLPALAPIPPAEVDGLEIRTGQKAYLRM
  QGFVESMKIILGGSMARVGALSECPFQGDESIHSAVTNALHSILGEQTKALVTQLTLFNQ
  ILVELRDDIRDQVKEMSLIRNTIMECQVCGFHEQRSHCSPNPCFRGVDCMEVYEYPGYRC
  GPCPPGLQGNGTHCSDINECAHADPCFPGSSCINTMPGFHCEACPRGYKGTQVSGVGIDY
  ARASKQVCNDIDECNDGNNGGCDPNSICTNTVGSFKCGPCRLGFLGNQSQGCLPARTCHS
  PAHSPCHIHAHCLFERNGAVSCQCNVGWAGNGNVCGTDTDIDGYPDQALPCMDNNKHCKQ
  DNCLLTPNSGQEDADNDGVGDQCDDDADGDGIKNVEDNCRLFPNKDQQNSDTDSFGDACD
  NCPNVPNNDQKDTDGNGEGDACDNDVDGDGIPNGLDNCPKVPNPLQTDRDEDGVGDACDS
  CPEMSNPTQTDADSDLVGDVCDTNEDSDGDGHQDTKDNCPQLPNSSQLDSDNDGLGDECD
  GDDDNDGIPDYVPPGPDNCRLVPNPNQKDSDGNGVGDVCEDDFDNDAVVDPLDVCPESAE
  VTLTDFRAYQTVVLDPEGDAQIDPNWVVLNQGMEIVQTMNSDPGLAVGYTAFNGVDFEGT
  FHVNTVTDDDYAGFLFSYQDSGRFYVVMWKQTEQTYWQATPFRAVAQPGLQLKAVTSVSG
  PGEHLRNALWHTGHTPDQVRLLWTDPRNVGWRDKTSYRWQLLHRPQVGYIRVKLYEGPQL
  VADSGVIIDTSMRGGRLGVFCFSQENIIWSNLQYRCNDTVPEDFEPFRRQLLQGRV
• Function: Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. Can bind to fibrinogen, fibronectin, laminin and type V collagen.
• KEGG Pathway:
  Phagosome (hsa04145)
  PI3K-Akt sig.ling pathway (hsa04151)
  Focal adhesion (hsa04510)
  ECM-receptor interaction (hsa04512)
  Cytoskeleton in muscle cells (hsa04820)
  Malaria (hsa05144)
  Human papillomavirus infection (hsa05165)
• Reactome Pathway: Signaling by PDGF (R-HSA-186797)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[1]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[2]
Gaucher disease	DISTW5JG	Strong	Biomarker	[3]
Mood disorder	DISLVMWO	Strong	Biomarker	[1]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[2]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[4]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[5]
Tourette syndrome	DISX9D54	No Known	Unknown	[6]

1 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 Thrombospondin-3 (THBS3).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Thrombospondin-3 (THBS3).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Thrombospondin-3 (THBS3).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Thrombospondin-3 (THBS3).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Thrombospondin-3 (THBS3).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Thrombospondin-3 (THBS3).	[12]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Thrombospondin-3 (THBS3).	[13]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Thrombospondin-3 (THBS3).	[14]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Thrombospondin-3 (THBS3).	[15]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Thrombospondin-3 (THBS3).	[16]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Thrombospondin-3 (THBS3).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Thrombospondin-3 (THBS3).	[18]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 increases the expression of Thrombospondin-3 (THBS3).	[15]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Thrombospondin-3 (THBS3).	[19]

References

• [1] Discovery of Biomarker Panels for Neural Dysfunction in Inborn Errors of Amino Acid Metabolism.Sci Rep. 2019 Jun 24;9(1):9128. doi: 10.1038/s41598-019-45674-2.
• [2] Effects of THBS3, SPARC and SPP1 expression on biological behavior and survival in patients with osteosarcoma.BMC Cancer. 2006 Oct 5;6:237. doi: 10.1186/1471-2407-6-237.
• [3] Metaxin, a gene contiguous to both thrombospondin 3 and glucocerebrosidase, is required for embryonic development in the mouse: implications for Gaucher disease.Proc Natl Acad Sci U S A. 1995 May 9;92(10):4547-51. doi: 10.1073/pnas.92.10.4547.
• [4] Meta-analysis of genome-wide association studies and functional assays decipher susceptibility genes for gastric cancer in Chinese populations.Gut. 2020 Apr;69(4):641-651. doi: 10.1136/gutjnl-2019-318760. Epub 2019 Aug 5.
• [5] Thrombospondin-3 augments injury-induced cardiomyopathy by intracellular integrin inhibition and sarcolemmal instability.Nat Commun. 2019 Jan 8;10(1):76. doi: 10.1038/s41467-018-08026-8.
• [6] 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.
• [7] 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.
• [8] Pretreatment of 3-MA prevents doxorubicin-induced cardiotoxicity through inhibition of autophagy initiation. Toxicology. 2023 May 15;490:153512. doi: 10.1016/j.tox.2023.153512. Epub 2023 Apr 14.
• [9] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [12] 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.
• [13] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [14] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [15] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.