Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSLHWF4)

• DOT Name: Mothers against decapentaplegic homolog 7 (SMAD7)
• Synonyms: MAD homolog 7; Mothers against DPP homolog 7; Mothers against decapentaplegic homolog 8; MAD homolog 8; Mothers against DPP homolog 8; SMAD family member 7; SMAD 7; Smad7; hSMAD7
• Gene Name: SMAD7
• UniProt ID: SMAD7_HUMAN
• PDB ID: 2DJY; 2KXQ; 2LTV; 2LTW; 2LTX; 2LTY; 2LTZ
• Pfam ID: PF03165 ; PF03166
• Sequence:
  MFRTKRSALVRRLWRSRAPGGEDEEEGAGGGGGGGELRGEGATDSRAHGAGGGGPGRAGC
  CLGKAVRGAKGHHHPHPPAAGAGAAGGAEADLKALTHSVLKKLKERQLELLLQAVESRGG
  TRTACLLLPGRLDCRLGPGAPAGAQPAQPPSSYSLPLLLCKVFRWPDLRHSSEVKRLCCC
  ESYGKINPELVCCNPHHLSRLCELESPPPPYSRYPMDFLKPTADCPDAVPSSAETGGTNY
  LAPGGLSDSQLLLEPGDRSHWCVVAYWEEKTRVGRLYCVQEPSLDIFYDLPQGNGFCLGQ
  LNSDNKSQLVQKVRSKIGCGIQLTREVDGVWVYNRSSYPIFIKSATLDNPDSRTLLVHKV
  FPGFSIKAFDYEKAYSLQRPNDHEFMQQPWTGFTVQISFVKGWGQCYTRQFISSCPCWLE
  VIFNSR
• Function: Antagonist of signaling by TGF-beta (transforming growth factor) type 1 receptor superfamily members; has been shown to inhibit TGF-beta (Transforming growth factor) and activin signaling by associating with their receptors thus preventing SMAD2 access. Functions as an adapter to recruit SMURF2 to the TGF-beta receptor complex. Also acts by recruiting the PPP1R15A-PP1 complex to TGFBR1, which promotes its dephosphorylation. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.
• Tissue Specificity: Ubiquitous with higher expression in the lung and vascular endothelium.
• KEGG Pathway:
  TGF-beta sig.ling pathway (hsa04350)
  Hippo sig.ling pathway (hsa04390)
• Reactome Pathway:
  Downregulation of TGF-beta receptor signaling (R-HSA-2173788)
  Downregulation of SMAD2/3 (R-HSA-2173795)
  SMAD2/SMAD3 (R-HSA-2173796)
  UCH proteinases (R-HSA-5689603)
  Ub-specific processing proteases (R-HSA-5689880)
  Interferon gamma signaling (R-HSA-877300)
  Signaling by BMP (R-HSA-201451)

Molecular Interaction Atlas (MIA) of This DOT

27 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 Mothers against decapentaplegic homolog 7 (SMAD7).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[13]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[14]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[15]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[17]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[18]
Glycyrrhizin	DM8M2N3	Phase 3	Glycyrrhizin increases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[22]
Acteoside	DM0YHKB	Terminated	Acteoside increases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[25]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[26]
Resorcinol	DMM37C0	Investigative	Resorcinol decreases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[27]
Galangin	DM5TQ2O	Investigative	Galangin decreases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[28]
Uric acid	DMA1MKT	Investigative	Uric acid decreases the expression of Mothers against decapentaplegic homolog 7 (SMAD7).	[29]

3 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 Mothers against decapentaplegic homolog 7 (SMAD7).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Mothers against decapentaplegic homolog 7 (SMAD7).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Mothers against decapentaplegic homolog 7 (SMAD7).	[23]

References

• [1] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] 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.
• [4] 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.
• [5] Doxorubicin inhibits TGF-beta signaling in human lung carcinoma A549 cells. Eur J Pharmacol. 2008 Aug 20;590(1-3):67-73. doi: 10.1016/j.ejphar.2008.05.030. Epub 2008 May 29.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] 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.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [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] 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] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [14] 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.
• [15] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [16] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [17] 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.
• [18] Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
• [19] Verbascoside inhibits the epithelial-mesenchymal transition of prostate cancer cells through high-mobility group box 1/receptor for advanced glycation end-products/TGF- pathway. Environ Toxicol. 2021 Jun;36(6):1080-1089. doi: 10.1002/tox.23107. Epub 2021 Feb 1.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] 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.
• [23] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [24] 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.
• [25] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [26] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [27] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [28] Galangin suppresses HepG2 cell proliferation by activating the TGF- receptor/Smad pathway. Toxicology. 2014 Dec 4;326:9-17. doi: 10.1016/j.tox.2014.09.010. Epub 2014 Sep 28.
• [29] TGF- is elevated in hyperuricemic individuals and mediates urate-induced hyperinflammatory phenotype in human mononuclear cells. Arthritis Res Ther. 2023 Feb 27;25(1):30. doi: 10.1186/s13075-023-03001-1.