Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4MKCC8)

• DOT Name: Protein Smaug homolog 1 (SAMD4A)
• Synonyms: Smaug 1; hSmaug1; Sterile alpha motif domain-containing protein 4A; SAM domain-containing protein 4A
• Gene Name: SAMD4A
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Alzheimer disease 3
  Drug dependence
  Metabolic bone disease
  Myopathy
  Neoplasm
  Osteoporosis
  Schizophrenia
  Substance abuse
  Substance dependence
  Atherosclerosis
• UniProt ID: SMAG1_HUMAN
• PDB ID: 8OIK
• Pfam ID: PF00536
• Sequence:
  MMFRDQVGVLAGWFKGWNECEQTVALLSLLKRVSQTQARFLQLCLEHSLADCAELHVLER
  EANSPGIINQWQQESKDKVISLLLTHLPLLKPGNLDAKVEYMKLLPKILAHSIEHNQHIE
  ESRQLLSYALIHPATSLEDRSALAMWLNHLEDRTSTSFGGQNRGRSDSVDYGQTHYYHQR
  QNSDDKLNGWQNSRDSGICINASNWQDKSMGCENGHVPLYSSSSVPTTINTIGTSTSTIL
  SGQAHHSPLKRSVSLTPPMNVPNQPLGHGWMSHEDLRARGPQCLPSDHAPLSPQSSVASS
  GSGGSEHLEDQTTARNTFQEEGSGMKDVPAWLKSLRLHKYAALFSQMTYEEMMALTECQL
  EAQNVTKGARHKIVISIQKLKERQNLLKSLERDIIEGGSLRIPLQELHQMILTPIKAYSS
  PSTTPEARRREPQAPRQPSLMGPESQSPDCKDGAAATGATATPSAGASGGLQPHQLSSCD
  GELAVAPLPEGDLPGQFTRVMGKVCTQLLVSRPDEENISSYLQLIDKCLIHEAFTETQKK
  RLLSWKQQVQKLFRSFPRKTLLDISGYRQQRNRGFGQSNSLPTAGSVGGGMGRRNPRQYQ
  IPSRNVPSARLGLLGTSGFVSSNQRNTTATPTIMKQGRQNLWFANPGGSNSMPSRTHSSV
  QRTRSLPVHTSPQNMLMFQQPEFQLPVTEPDINNRLESLCLSMTEHALGDGVDRTSTI
• Function: Acts as a translational repressor of SRE-containing messengers.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Alzheimer disease 3	DISVT69G	Strong	Biomarker	[2]
Drug dependence	DIS9IXRC	Strong	Biomarker	[3]
Metabolic bone disease	DISO7RI8	Strong	Biomarker	[4]
Myopathy	DISOWG27	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Osteoporosis	DISF2JE0	Strong	Biomarker	[4]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[7]
Substance abuse	DIS327VW	Strong	Biomarker	[3]
Substance dependence	DISDRAAR	Strong	Biomarker	[3]
Atherosclerosis	DISMN9J3	Limited	Genetic Variation	[8]

19 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 Protein Smaug homolog 1 (SAMD4A).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein Smaug homolog 1 (SAMD4A).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein Smaug homolog 1 (SAMD4A).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein Smaug homolog 1 (SAMD4A).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein Smaug homolog 1 (SAMD4A).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein Smaug homolog 1 (SAMD4A).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein Smaug homolog 1 (SAMD4A).	[15]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Protein Smaug homolog 1 (SAMD4A).	[16]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Protein Smaug homolog 1 (SAMD4A).	[17]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein Smaug homolog 1 (SAMD4A).	[18]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Protein Smaug homolog 1 (SAMD4A).	[19]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Protein Smaug homolog 1 (SAMD4A).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Protein Smaug homolog 1 (SAMD4A).	[22]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Protein Smaug homolog 1 (SAMD4A).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein Smaug homolog 1 (SAMD4A).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein Smaug homolog 1 (SAMD4A).	[27]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Protein Smaug homolog 1 (SAMD4A).	[28]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Protein Smaug homolog 1 (SAMD4A).	[29]
Resorcinol	DMM37C0	Investigative	Resorcinol decreases the expression of Protein Smaug homolog 1 (SAMD4A).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protein Smaug homolog 1 (SAMD4A).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Protein Smaug homolog 1 (SAMD4A).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Protein Smaug homolog 1 (SAMD4A).	[26]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Protein Smaug homolog 1 (SAMD4A).	[25]

References

• [1] Circular RNA CpG island hypermethylation-associated silencing in human cancer.Oncotarget. 2018 Jun 26;9(49):29208-29219. doi: 10.18632/oncotarget.25673. eCollection 2018 Jun 26.
• [2] Functional segregation of executive control network and frontoparietal network in Alzheimer's disease.Cortex. 2019 Nov;120:36-48. doi: 10.1016/j.cortex.2019.04.026. Epub 2019 May 18.
• [3] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [4] RNA-binding protein SAMD4 regulates skeleton development through translational inhibition of Mig6 expression.Cell Discov. 2017 Jan 24;3:16050. doi: 10.1038/celldisc.2016.50. eCollection 2017.
• [5] Smaug/SAMD4A restores translational activity of CUGBP1 and suppresses CUG-induced myopathy.PLoS Genet. 2013 Apr;9(4):e1003445. doi: 10.1371/journal.pgen.1003445. Epub 2013 Apr 18.
• [6] Vaccination efficacy with marrow mesenchymal stem cell against cancer was enhanced under simulated microgravity.Biochem Biophys Res Commun. 2017 Apr 8;485(3):606-613. doi: 10.1016/j.bbrc.2017.01.136. Epub 2017 Feb 24.
• [7] Genome-wide association study of paliperidone efficacy.Pharmacogenet Genomics. 2017 Jan;27(1):7-18. doi: 10.1097/FPC.0000000000000250.
• [8] Identification of the BCAR1-CFDP1-TMEM170A locus as a determinant of carotid intima-media thickness and coronary artery disease risk.Circ Cardiovasc Genet. 2012 Dec;5(6):656-65. doi: 10.1161/CIRCGENETICS.112.963660. Epub 2012 Nov 14.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] 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.
• [11] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [12] 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.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [16] Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
• [17] 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.
• [18] 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.
• [19] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [20] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [21] 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.
• [22] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [23] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [29] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [30] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.