Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6EOLFC)

• DOT Name: Melanoma-associated antigen D1 (MAGED1)
• Synonyms: MAGE tumor antigen CCF; MAGE-D1 antigen; Neurotrophin receptor-interacting MAGE homolog
• Gene Name: MAGED1
• Related Disease:
  Intellectual disability
  Advanced cancer
  B-cell neoplasm
  Brain neoplasm
  Carcinoma of esophagus
  Clear cell renal carcinoma
  Depression
  Drug dependence
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Glioma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Neoplasm of esophagus
  Non-small-cell lung cancer
  Obesity
  Pancreatic cancer
  Pancreatic tumour
  Prader-Willi syndrome
  Prostate cancer
  Renal cell carcinoma
  Melanoma
  Anxiety
  Anxiety disorder
  Autism
• UniProt ID: MAGD1_HUMAN
• Pfam ID: PF01454
• Sequence:
  MAQKMDCGAGLLGFQAEASVEDSALLMQTLMEAIQISEAPPTNQATAAASPQSSQPPTAN
  EMADIQVSAAAARPKSAFKVQNATTKGPNGVYDFSQAHNAKDVPNTQPKAAFKSQNATPK
  GPNAAYDFSQAATTGELAANKSEMAFKAQNATTKVGPNATYNFSQSLNANDLANSRPKTP
  FKAWNDTTKAPTADTQTQNVNQAKMATSQADIETDPGISEPDGATAQTSADGSQAQNLES
  RTIIRGKRTRKINNLNVEENSSGDQRRAPLAAGTWRSAPVPVTTQNPPGAPPNVLWQTPL
  AWQNPSGWQNQTARQTPPARQSPPARQTPPAWQNPVAWQNPVIWPNPVIWQNPVIWPNPI
  VWPGPVVWPNPLAWQNPPGWQTPPGWQTPPGWQGPPDWQGPPDWPLPPDWPLPPDWPLPT
  DWPLPPDWIPADWPIPPDWQNLRPSPNLRPSPNSRASQNPGAAQPRDVALLQERANKLVK
  YLMLKDYTKVPIKRSEMLRDIIREYTDVYPEIIERACFVLEKKFGIQLKEIDKEEHLYIL
  ISTPESLAGILGTTKDTPKLGLLLVILGVIFMNGNRASEAVLWEALRKMGLRPGVRHPLL
  GDLRKLLTYEFVKQKYLDYRRVPNSNPPEYEFLWGLRSYHETSKMKVLRFIAEVQKRDPR
  DWTAQFMEAADEALDALDAAAAEAEARAEARTRMGIGDEAVSGPWSWDDIEFELLTWDEE
  GDFGDPWSRIPFTFWARYHQNARSRFPQTFAGPIIGPGGTASANFAANFGAIGFFWVE
• Function: Involved in the apoptotic response after nerve growth factor (NGF) binding in neuronal cells. Inhibits cell cycle progression, and facilitates NGFR-mediated apoptosis. May act as a regulator of the function of DLX family members. May enhance ubiquitin ligase activity of RING-type zinc finger-containing E3 ubiquitin-protein ligases. Proposed to act through recruitment and/or stabilization of the Ubl-conjugating enzyme (E2) at the E3:substrate complex. Plays a role in the circadian rhythm regulation. May act as RORA co-regulator, modulating the expression of core clock genes such as BMAL1 and NFIL3, induced, or NR1D1, repressed.
• Tissue Specificity: Expressed in bone marrow stromal cells from both multiple myeloma patients and healthy donors. Seems to be ubiquitously expressed.
• KEGG Pathway: Neurotrophin sig.ling pathway (hsa04722)
• Reactome Pathway:
  Caspase activation via Dependence Receptors in the absence of ligand (R-HSA-418889)
  NPAS4 regulates expression of target genes (R-HSA-9768919)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
B-cell neoplasm	DISVY326	Strong	Biomarker	[3]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[2]
Carcinoma of esophagus	DISS6G4D	Strong	Altered Expression	[4]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[5]
Depression	DIS3XJ69	Strong	Biomarker	[6]
Drug dependence	DIS9IXRC	Strong	Biomarker	[7]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[8]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[8]
Glioma	DIS5RPEH	Strong	Biomarker	[2]
Lung cancer	DISCM4YA	Strong	Biomarker	[9]
Lung carcinoma	DISTR26C	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[9]
Obesity	DIS47Y1K	Strong	Biomarker	[10]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[11]
Pancreatic tumour	DIS3U0LK	Strong	Altered Expression	[11]
Prader-Willi syndrome	DISYWMLU	Strong	Biomarker	[12]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[13]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[5]
Melanoma	DIS1RRCY	moderate	Altered Expression	[11]
Anxiety	DISIJDBA	Limited	Biomarker	[14]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[14]
Autism	DISV4V1Z	Limited	Biomarker	[14]

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Melanoma-associated antigen D1 (MAGED1) affects the response to substance of Methotrexate.	[30]
Fluorouracil	DMUM7HZ	Approved	Melanoma-associated antigen D1 (MAGED1) affects the response to substance of Fluorouracil.	[31]
Topotecan	DMP6G8T	Approved	Melanoma-associated antigen D1 (MAGED1) affects the response to substance of Topotecan.	[30]
Mitoxantrone	DMM39BF	Approved	Melanoma-associated antigen D1 (MAGED1) affects the response to substance of Mitoxantrone.	[30]
Cyclophosphamide	DM4O2Z7	Approved	Melanoma-associated antigen D1 (MAGED1) affects the response to substance of Cyclophosphamide.	[30]

15 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 Melanoma-associated antigen D1 (MAGED1).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Melanoma-associated antigen D1 (MAGED1).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Melanoma-associated antigen D1 (MAGED1).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Melanoma-associated antigen D1 (MAGED1).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Melanoma-associated antigen D1 (MAGED1).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Melanoma-associated antigen D1 (MAGED1).	[20]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Melanoma-associated antigen D1 (MAGED1).	[21]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Melanoma-associated antigen D1 (MAGED1).	[22]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Melanoma-associated antigen D1 (MAGED1).	[23]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Melanoma-associated antigen D1 (MAGED1).	[24]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Melanoma-associated antigen D1 (MAGED1).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Melanoma-associated antigen D1 (MAGED1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Melanoma-associated antigen D1 (MAGED1).	[27]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Melanoma-associated antigen D1 (MAGED1).	[28]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR decreases the expression of Melanoma-associated antigen D1 (MAGED1).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Melanoma-associated antigen D1 (MAGED1).	[26]

References

• [1] Xp11.22 deletions encompassing CENPVL1, CENPVL2, MAGED1 and GSPT2 as a cause of syndromic X-linked intellectual disability.PLoS One. 2017 Apr 17;12(4):e0175962. doi: 10.1371/journal.pone.0175962. eCollection 2017.
• [2] Dlxin-1, a member of MAGE family, inhibits cell proliferation, invasion and tumorigenicity of glioma stem cells.Cancer Gene Ther. 2011 Mar;18(3):206-18. doi: 10.1038/cgt.2010.71. Epub 2010 Nov 26.
• [3] Recurrent intragenic exon rearrangements of SOBP and AUTS2 in non-Hodgkin B-cell lymphoma.Int J Hematol. 2020 Jan;111(1):75-83. doi: 10.1007/s12185-019-02766-z. Epub 2019 Nov 4.
• [4] The role of NRAGE subcellular location and epithelial-mesenchymal transition on radiation resistance of esophageal carcinoma cell.J Cancer Res Ther. 2018 Jan;14(1):46-51. doi: 10.4103/jcrt.JCRT_687_17.
• [5] MAGED4-expression in renal cell carcinoma and identification of an HLA-A*25-restricted MHC class I ligand from solid tumor tissue.Cancer Biol Ther. 2005 Sep;4(9):943-8. doi: 10.4161/cbt.4.9.1907. Epub 2005 Sep 8.
• [6] Maged1 co-interacting with CREB through a hexapeptide repeat domain regulates learning and memory in mice.Mol Neurobiol. 2015 Feb;51(1):8-18. doi: 10.1007/s12035-014-8677-x. Epub 2014 Apr 4.
• [7] Deletion of Maged1 in mice abolishes locomotor and reinforcing effects of cocaine.EMBO Rep. 2018 Sep;19(9):e45089. doi: 10.15252/embr.201745089. Epub 2018 Jul 12.
• [8] Identification of novel NRAGE involved in the radioresistance of esophageal cancer cells.Tumour Biol. 2016 Jul;37(7):8741-52. doi: 10.1007/s13277-015-4747-6. Epub 2016 Jan 7.
• [9] Silencing of NRAGE induces autophagy via AMPK/Ulk1/Atg13 signaling pathway in NSCLC cells.Tumour Biol. 2017 Jun;39(6):1010428317709676. doi: 10.1177/1010428317709676.
• [10] Inhibition of PPAR, adipogenesis and insulin sensitivity by MAGED1.J Endocrinol. 2018 Nov 1;239(2):167-180. doi: 10.1530/JOE-18-0349.
• [11] NRAGE suppresses metastasis of melanoma and pancreatic cancer in vitro and in vivo.Cancer Lett. 2007 Jun 8;250(2):268-75. doi: 10.1016/j.canlet.2006.10.020. Epub 2006 Nov 30.
• [12] The roles of MAGE-D1 in the neuronal functions and pathology of the central nervous system.Rev Neurosci. 2013;24(1):61-70. doi: 10.1515/revneuro-2012-0069.
• [13] Multiple newly identified loci associated with prostate cancer susceptibility.Nat Genet. 2008 Mar;40(3):316-21. doi: 10.1038/ng.90. Epub 2008 Feb 10.
• [14] Loss of Maged1 results in obesity, deficits of social interactions, impaired sexual behavior and severe alteration of mature oxytocin production in the hypothalamus.Hum Mol Genet. 2012 Nov 1;21(21):4703-17. doi: 10.1093/hmg/dds310. Epub 2012 Aug 2.
• [15] 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.
• [16] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [17] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [18] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [21] 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.
• [22] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [23] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [24] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [25] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [26] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [27] Genome-wide gene expression profiling of low-dose, long-term exposure of human osteosarcoma cells to bisphenol A and its analogs bisphenols AF and S. Toxicol In Vitro. 2015 Aug;29(5):1060-9.
• [28] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [29] Gene expression network regulated by DNA methylation and microRNA during microcystin-leucine arginine induced malignant transformation in human hepatocyte L02 cells. Toxicol Lett. 2018 Jun 1;289:42-53. doi: 10.1016/j.toxlet.2018.03.003. Epub 2018 Mar 5.
• [30] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [31] Mechanistic and predictive profiling of 5-Fluorouracil resistance in human cancer cells. Cancer Res. 2004 Nov 15;64(22):8167-76. doi: 10.1158/0008-5472.CAN-04-0970.