Details of Drug Off-Target (DOT)

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

• DOT Name: Mothers against decapentaplegic homolog 6 (SMAD6)
• Synonyms: MAD homolog 6; Mothers against DPP homolog 6; SMAD family member 6; SMAD 6; Smad6; hSMAD6
• Gene Name: SMAD6
• Related Disease:
  Craniosynostosis 7
  Radioulnar synostosis, nonsyndromic, susceptibility to
  Aortic valve disease 2
  Congenital radioulnar synostosis
  Familial bicuspid aortic valve
• UniProt ID: SMAD6_HUMAN
• Pfam ID: PF03165 ; PF03166
• Sequence:
  MFRSKRSGLVRRLWRSRVVPDREEGGSGGGGGGDEDGSLGSRAEPAPRAREGGGCGRSEV
  RPVAPRRPRDAVGQRGAQGAGRRRRAGGPPRPMSEPGAGAGSSLLDVAEPGGPGWLPESD
  CETVTCCLFSERDAAGAPRDASDPLAGAALEPAGGGRSREARSRLLLLEQELKTVTYSLL
  KRLKERSLDTLLEAVESRGGVPGGCVLVPRADLRLGGQPAPPQLLLGRLFRWPDLQHAVE
  LKPLCGCHSFAAAADGPTVCCNPYHFSRLCGPESPPPPYSRLSPRDEYKPLDLSDSTLSY
  TETEATNSLITAPGEFSDASMSPDATKPSHWCSVAYWEHRTRVGRLYAVYDQAVSIFYDL
  PQGSGFCLGQLNLEQRSESVRRTRSKIGFGILLSKEPDGVWAYNRGEHPIFVNSPTLDAP
  GGRALVVRKVPPGYSIKVFDFERSGLQHAPEPDAADGPYDPNSVRISFAKGWGPCYSRQF
  ITSCPCWLEILLNNPR
• Function: Transforming growth factor-beta superfamily receptors signaling occurs through the Smad family of intracellular mediators. SMAD6 is an inhibitory Smad (i-Smad) that negatively regulates signaling downstream of type I transforming growth factor-beta. Acts as a mediator of TGF-beta and BMP anti-inflammatory activities. Suppresses IL1R-TLR signaling through its direct interaction with PEL1, preventing NF-kappa-B activation, nuclear transport and NF-kappa-B-mediated expression of pro-inflammatory genes. Blocks the BMP-SMAD1 signaling pathway by competing with SMAD4 for receptor-activated SMAD1-binding. Binds to regulatory elements in target promoter regions.
• Tissue Specificity: .Expressed in the brain, heart, ovary, peripheral blood leukocytes, small intestine, spleen, thymus, bone marrow, fetal liver and lymph nodes.
• KEGG Pathway: TGF-beta sig.ling pathway (hsa04350)
• Reactome Pathway:
  RUNX2 regulates bone development (R-HSA-8941326)
  Signaling by BMP (R-HSA-201451)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Craniosynostosis 7	DIS3AZPM	Strong	Autosomal dominant	[1]
Radioulnar synostosis, nonsyndromic, susceptibility to	DISAMEIF	Strong	Autosomal dominant	[2]
Aortic valve disease 2	DISOMB0X	Moderate	Autosomal dominant	[2]
Congenital radioulnar synostosis	DISF96QX	Supportive	Unknown	[3]
Familial bicuspid aortic valve	DISL0BRK	Supportive	Autosomal dominant	[4]

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 Mothers against decapentaplegic homolog 6 (SMAD6).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mothers against decapentaplegic homolog 6 (SMAD6).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Mothers against decapentaplegic homolog 6 (SMAD6).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mothers against decapentaplegic homolog 6 (SMAD6).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Mothers against decapentaplegic homolog 6 (SMAD6).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Mothers against decapentaplegic homolog 6 (SMAD6).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Mothers against decapentaplegic homolog 6 (SMAD6).	[11]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Mothers against decapentaplegic homolog 6 (SMAD6).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Mothers against decapentaplegic homolog 6 (SMAD6).	[13]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Mothers against decapentaplegic homolog 6 (SMAD6).	[14]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Mothers against decapentaplegic homolog 6 (SMAD6).	[15]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of Mothers against decapentaplegic homolog 6 (SMAD6).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mothers against decapentaplegic homolog 6 (SMAD6).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mothers against decapentaplegic homolog 6 (SMAD6).	[18]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Mothers against decapentaplegic homolog 6 (SMAD6).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Mothers against decapentaplegic homolog 6 (SMAD6).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Mothers against decapentaplegic homolog 6 (SMAD6).	[21]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of Mothers against decapentaplegic homolog 6 (SMAD6).	[22]
Galangin	DM5TQ2O	Investigative	Galangin decreases the expression of Mothers against decapentaplegic homolog 6 (SMAD6).	[23]

References

• [1] SMAD6 variants in craniosynostosis: genotype and phenotype evaluation. Genet Med. 2020 Sep;22(9):1498-1506. doi: 10.1038/s41436-020-0817-2. Epub 2020 Jun 5.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] SMAD6 is frequently mutated in nonsyndromic radioulnar synostosis. Genet Med. 2019 Nov;21(11):2577-2585. doi: 10.1038/s41436-019-0552-8. Epub 2019 May 29.
• [4] Nonsynonymous variants in the SMAD6 gene predispose to congenital cardiovascular malformation. Hum Mutat. 2012 Apr;33(4):720-7. doi: 10.1002/humu.22030. Epub 2012 Feb 14.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 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.
• [10] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [11] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [14] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [15] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [16] The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time-dependent. Toxicology. 2010 Apr 11;270(2-3):137-49. doi: 10.1016/j.tox.2010.02.008. Epub 2010 Feb 17.
• [17] Effect of benzo[a]pyrene on proliferation and metastasis of oral squamous cell carcinoma cells: A transcriptome analysis based on RNA-seq. Environ Toxicol. 2022 Nov;37(11):2589-2604. doi: 10.1002/tox.23621. Epub 2022 Jul 23.
• [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] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [20] 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.
• [21] 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.
• [22] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [23] 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.