Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQSHR25)

• DOT Name: Mothers against decapentaplegic homolog 1 (SMAD1)
• Synonyms: MAD homolog 1; Mothers against DPP homolog 1; JV4-1; Mad-related protein 1; SMAD family member 1; SMAD 1; Smad1; hSMAD1; Transforming growth factor-beta-signaling protein 1; BSP-1
• Gene Name: SMAD1
• Related Disease: Pulmonary arterial hypertension
• UniProt ID: SMAD1_HUMAN
• PDB ID: 1KHU; 2LAW; 2LAX; 2LAY; 2LAZ; 2LB0; 2LB1; 3Q47; 3Q4A; 5ZOK
• Pfam ID: PF03165 ; PF03166
• Sequence:
  MNVTSLFSFTSPAVKRLLGWKQGDEEEKWAEKAVDALVKKLKKKKGAMEELEKALSCPGQ
  PSNCVTIPRSLDGRLQVSHRKGLPHVIYCRVWRWPDLQSHHELKPLECCEFPFGSKQKEV
  CINPYHYKRVESPVLPPVLVPRHSEYNPQHSLLAQFRNLGQNEPHMPLNATFPDSFQQPN
  SHPFPHSPNSSYPNSPGSSSSTYPHSPTSSDPGSPFQMPADTPPPAYLPPEDPMTQDGSQ
  PMDTNMMAPPLPSEINRGDVQAVAYEEPKHWCSIVYYELNNRVGEAFHASSTSVLVDGFT
  DPSNNKNRFCLGLLSNVNRNSTIENTRRHIGKGVHLYYVGGEVYAECLSDSSIFVQSRNC
  NYHHGFHPTTVCKIPSGCSLKIFNNQEFAQLLAQSVNHGFETVYELTKMCTIRMSFVKGW
  GAEYHRQDVTSTPCWIEIHLHGPLQWLDKVLTQMGSPHNPISSVS
• Function: Transcriptional modulator that plays a role in various cellular processes, including embryonic development, cell differentiation, and tissue homeostasis. Upon BMP ligand binding to their receptors at the cell surface, is phosphorylated by activated type I BMP receptors (BMPRIs) and associates with SMAD4 to form an heteromeric complex which translocates into the nucleus acting as transcription factor. In turn, the hetero-trimeric complex recognizes cis-regulatory elements containing Smad Binding Elements (SBEs) to modulate the outcome of the signaling network. SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1. Positively regulates BMP4-induced expression of odontogenic development regulator MSX1 following IPO7-mediated nuclear import.
• Tissue Specificity: Ubiquitous. Highest expression seen in the heart and skeletal muscle.
• KEGG Pathway:
  TGF-beta sig.ling pathway (hsa04350)
  Hippo sig.ling pathway (hsa04390)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
  Transcriptio.l misregulation in cancer (hsa05202)
• Reactome Pathway:
  Ub-specific processing proteases (R-HSA-5689880)
  RUNX2 regulates bone development (R-HSA-8941326)
  Cardiogenesis (R-HSA-9733709)
  Signaling by BMP (R-HSA-201451)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pulmonary arterial hypertension	DISP8ZX5	Disputed	Autosomal dominant	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Prednisolone	DMQ8FR2	Approved	Mothers against decapentaplegic homolog 1 (SMAD1) increases the Metabolic disorder ADR of Prednisolone.	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Mothers against decapentaplegic homolog 1 (SMAD1).	[2]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the phosphorylation of Mothers against decapentaplegic homolog 1 (SMAD1).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mothers against decapentaplegic homolog 1 (SMAD1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mothers against decapentaplegic homolog 1 (SMAD1).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Mothers against decapentaplegic homolog 1 (SMAD1).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Mothers against decapentaplegic homolog 1 (SMAD1).	[6]
Marinol	DM70IK5	Approved	Marinol increases the expression of Mothers against decapentaplegic homolog 1 (SMAD1).	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Mothers against decapentaplegic homolog 1 (SMAD1).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Mothers against decapentaplegic homolog 1 (SMAD1).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Mothers against decapentaplegic homolog 1 (SMAD1).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Mothers against decapentaplegic homolog 1 (SMAD1).	[12]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Mothers against decapentaplegic homolog 1 (SMAD1).	[13]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Mothers against decapentaplegic homolog 1 (SMAD1).	[14]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Mothers against decapentaplegic homolog 1 (SMAD1).	[15]
Galangin	DM5TQ2O	Investigative	Galangin increases the expression of Mothers against decapentaplegic homolog 1 (SMAD1).	[16]
ROLIPRAM	DMJ03UM	Investigative	ROLIPRAM decreases the expression of Mothers against decapentaplegic homolog 1 (SMAD1).	[17]
LY2109761	DMAWTG3	Investigative	LY2109761 decreases the expression of Mothers against decapentaplegic homolog 1 (SMAD1).	[18]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] 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.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [7] 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.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [9] 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.
• [10] 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.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] 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.
• [13] 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.
• [14] Reversal of Sp1 transactivation and TGF1/SMAD1 signaling by H(2)S prevent nickel-induced fibroblast activation. Toxicol Appl Pharmacol. 2018 Oct 1;356:25-35. doi: 10.1016/j.taap.2018.07.029. Epub 2018 Jul 26.
• [15] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [16] 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.
• [17] Rolipram suppresses migration and invasion of human choriocarcinoma cells by inhibiting phosphodiesterase 4-mediated epithelial-mesenchymal transition. J Biochem Mol Toxicol. 2023 Jul;37(7):e23363. doi: 10.1002/jbt.23363. Epub 2023 Apr 5.
• [18] In vitro and ex vivo anti-fibrotic effects of LY2109761, a small molecule inhibitor against TGF-. Toxicol Appl Pharmacol. 2018 Sep 15;355:127-137. doi: 10.1016/j.taap.2018.07.001. Epub 2018 Jul 3.
• [19] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.