Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK4M1H8)

• DOT Name: Mothers against decapentaplegic homolog 9 (SMAD9)
• Synonyms: MAD homolog 9; Mothers against DPP homolog 9; Madh6; SMAD family member 9; SMAD 9; Smad9
• Gene Name: SMAD9
• Related Disease:
  Pulmonary arterial hypertension
  Pulmonary hypertension, primary, 2
  Heritable pulmonary arterial hypertension
• UniProt ID: SMAD9_HUMAN
• PDB ID: 6FZT
• Pfam ID: PF03165 ; PF03166
• Sequence:
  MHSTTPISSLFSFTSPAVKRLLGWKQGDEEEKWAEKAVDSLVKKLKKKKGAMDELERALS
  CPGQPSKCVTIPRSLDGRLQVSHRKGLPHVIYCRVWRWPDLQSHHELKPLECCEFPFGSK
  QKEVCINPYHYRRVETPVLPPVLVPRHSEYNPQLSLLAKFRSASLHSEPLMPHNATYPDS
  FQQPPCSALPPSPSHAFSQSPCTASYPHSPGSPSEPESPYQHSVDTPPLPYHATEASETQ
  SGQPVDATADRHVVLSIPNGDFRPVCYEEPQHWCSVAYYELNNRVGETFQASSRSVLIDG
  FTDPSNNRNRFCLGLLSNVNRNSTIENTRRHIGKGVHLYYVGGEVYAECVSDSSIFVQSR
  NCNYQHGFHPATVCKIPSGCSLKVFNNQLFAQLLAQSVHHGFEVVYELTKMCTIRMSFVK
  GWGAEYHRQDVTSTPCWIEIHLHGPLQWLDKVLTQMGSPHNPISSVS
• Function: Transcriptional modulator activated by BMP (bone morphogenetic proteins) type 1 receptor kinase. SMAD9 is a receptor-regulated SMAD (R-SMAD).
• Tissue Specificity: Expressed in heart, brain, placenta, lung, skeletal muscle, prostate, testis, ovary and small intestine. Also expressed in fetal brain, lung and kidney.
• KEGG Pathway:
  TGF-beta sig.ling pathway (hsa04350)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
• Reactome Pathway: Signaling by BMP (R-HSA-201451)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pulmonary arterial hypertension	DISP8ZX5	Definitive	Autosomal dominant	[1]
Pulmonary hypertension, primary, 2	DIS7TSNY	Strong	Autosomal dominant	[2]
Heritable pulmonary arterial hypertension	DISD1Y94	Supportive	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Mothers against decapentaplegic homolog 9 (SMAD9).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mothers against decapentaplegic homolog 9 (SMAD9).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Mothers against decapentaplegic homolog 9 (SMAD9).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mothers against decapentaplegic homolog 9 (SMAD9).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mothers against decapentaplegic homolog 9 (SMAD9).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Mothers against decapentaplegic homolog 9 (SMAD9).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Mothers against decapentaplegic homolog 9 (SMAD9).	[10]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Mothers against decapentaplegic homolog 9 (SMAD9).	[11]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Mothers against decapentaplegic homolog 9 (SMAD9).	[12]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Mothers against decapentaplegic homolog 9 (SMAD9).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Mothers against decapentaplegic homolog 9 (SMAD9).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mothers against decapentaplegic homolog 9 (SMAD9).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Mothers against decapentaplegic homolog 9 (SMAD9).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mothers against decapentaplegic homolog 9 (SMAD9).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Mothers against decapentaplegic homolog 9 (SMAD9).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Mothers against decapentaplegic homolog 9 (SMAD9).	[21]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the phosphorylation of Mothers against decapentaplegic homolog 9 (SMAD9).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Mothers against decapentaplegic homolog 9 (SMAD9).	[19]

References

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• [2] A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension. J Med Genet. 2009 May;46(5):331-7. doi: 10.1136/jmg.2008.062703. Epub 2009 Feb 11.
• [3] Altered MicroRNA processing in heritable pulmonary arterial hypertension: an important role for Smad-8. Am J Respir Crit Care Med. 2011 Dec 15;184(12):1400-8. doi: 10.1164/rccm.201106-1130OC. Epub 2011 Sep 15.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [8] 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.
• [9] Prenatal arsenic exposure and shifts in the newborn proteome: interindividual differences in tumor necrosis factor (TNF)-responsive signaling. Toxicol Sci. 2014 Jun;139(2):328-37. doi: 10.1093/toxsci/kfu053. Epub 2014 Mar 27.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [12] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [13] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [14] 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.
• [15] The role of sirtuin 1 in osteoblastic differentiation in human periodontal ligament cells. J Periodontal Res. 2011 Dec;46(6):712-21. doi: 10.1111/j.1600-0765.2011.01394.x. Epub 2011 Jul 11.
• [16] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [20] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [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.