Details of Drug Off-Target (DOT)

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

• DOT Name: Melanoma-associated antigen D2 (MAGED2)
• Synonyms: 11B6; Breast cancer-associated gene 1 protein; BCG-1; Hepatocellular carcinoma-associated protein JCL-1; MAGE-D2 antigen
• Gene Name: MAGED2
• Related Disease:
  X-linked intellectual disability
  Advanced cancer
  Appendicitis
  Bartter disease type 1
  Bartter disease type 5
  Bartter syndrome
  Breast cancer
  Colorectal carcinoma
  Diabetes insipidus, nephrogenic, X-linked
  Gastric cancer
  Her2-receptor negative breast cancer
  Metastatic malignant neoplasm
  Nephropathy
  Stomach cancer
  Breast carcinoma
  Carcinoid tumor
  Gastric neoplasm
  Melanoma
  Obsolete antenatal Bartter syndrome
  Carcinoma
• UniProt ID: MAGD2_HUMAN
• Pfam ID: PF01454
• Sequence:
  MSDTSESGAGLTRFQAEASEKDSSSMMQTLLTVTQNVEVPETPKASKALEVSEDVKVSKA
  SGVSKATEVSKTPEAREAPATQASSTTQLTDTQVLAAENKSLAADTKKQNADPQAVTMPA
  TETKKVSHVADTKVNTKAQETEAAPSQAPADEPEPESAAAQSQENQDTRPKVKAKKARKV
  KHLDGEEDGSSDQSQASGTTGGRRVSKALMASMARRASRGPIAFWARRASRTRLAAWARR
  ALLSLRSPKARRGKARRRAAKLQSSQEPEAPPPRDVALLQGRANDLVKYLLAKDQTKIPI
  KRSDMLKDIIKEYTDVYPEIIERAGYSLEKVFGIQLKEIDKNDHLYILLSTLEPTDAGIL
  GTTKDSPKLGLLMVLLSIIFMNGNRSSEAVIWEVLRKLGLRPGIHHSLFGDVKKLITDEF
  VKQKYLDYARVPNSNPPEYEFFWGLRSYYETSKMKVLKFACKVQKKDPKEWAAQYREAME
  ADLKAAAEAAAEAKARAEIRARMGIGLGSENAAGPCNWDEADIGPWAKARIQAGAEAKAK
  AQESGSASTGASTSTNNSASASASTSGGFSAGASLTATLTFGLFAGLGGAGASTSGSSGA
  CGFSYK
• Function: Regulates the expression, localization to the plasma membrane and function of the sodium chloride cotransporters SLC12A1 and SLC12A3, two key components of salt reabsorption in the distal renal tubule.
• Tissue Specificity: Widely expressed. In the developing and adult kidney, expressed in the thick ascending limb of the loop of Henle and the distal convoluted tubules outside the loop.
• Reactome Pathway: Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
X-linked intellectual disability	DISYJBY3	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Appendicitis	DIS4GOLF	Strong	Altered Expression	[3]
Bartter disease type 1	DISV9S4X	Strong	GermlineCausalMutation	[4]
Bartter disease type 5	DISX9RPI	Strong	X-linked	[4]
Bartter syndrome	DIS7D44B	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[7]
Diabetes insipidus, nephrogenic, X-linked	DISHUTO5	Strong	Genetic Variation	[8]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[7]
Her2-receptor negative breast cancer	DISS605N	Strong	Biomarker	[9]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[10]
Nephropathy	DISXWP4P	Strong	Biomarker	[11]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[7]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[6]
Carcinoid tumor	DISMNRDC	moderate	Biomarker	[12]
Gastric neoplasm	DISOKN4Y	moderate	Altered Expression	[12]
Melanoma	DIS1RRCY	moderate	Biomarker	[13]
Obsolete antenatal Bartter syndrome	DIS5WI27	Supportive	Autosomal recessive	[4]
Carcinoma	DISH9F1N	Limited	Altered Expression	[14]

13 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 D2 (MAGED2).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Melanoma-associated antigen D2 (MAGED2).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Melanoma-associated antigen D2 (MAGED2).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Melanoma-associated antigen D2 (MAGED2).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Melanoma-associated antigen D2 (MAGED2).	[20]
Selenium	DM25CGV	Approved	Selenium increases the expression of Melanoma-associated antigen D2 (MAGED2).	[21]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Melanoma-associated antigen D2 (MAGED2).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Melanoma-associated antigen D2 (MAGED2).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Melanoma-associated antigen D2 (MAGED2).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Melanoma-associated antigen D2 (MAGED2).	[26]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Melanoma-associated antigen D2 (MAGED2).	[27]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Melanoma-associated antigen D2 (MAGED2).	[28]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of Melanoma-associated antigen D2 (MAGED2).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Melanoma-associated antigen D2 (MAGED2).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Melanoma-associated antigen D2 (MAGED2).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Melanoma-associated antigen D2 (MAGED2).	[24]

References

• [1] Expression pattern and further characterization of human MAGED2 and identification of rodent orthologues.Cytogenet Cell Genet. 2001;94(3-4):233-40. doi: 10.1159/000048822.
• [2] Melanoma antigen-D2 controls cell cycle progression and modulates the DNA damage response.Biochem Pharmacol. 2018 Jul;153:217-229. doi: 10.1016/j.bcp.2018.01.035. Epub 2018 Feb 1.
• [3] Genetic differentiation of appendiceal tumor malignancy: a guide for the perplexed.Ann Surg. 2006 Jul;244(1):52-60. doi: 10.1097/01.sla.0000217617.06782.d5.
• [4] Polyhydramnios, Transient Antenatal Bartter's Syndrome, and MAGED2 Mutations. N Engl J Med. 2016 May 12;374(19):1853-63. doi: 10.1056/NEJMoa1507629. Epub 2016 Apr 27.
• [5] MAGED2: a novel form of antenatal Bartter's syndrome.Curr Opin Nephrol Hypertens. 2018 Jul;27(4):323-328. doi: 10.1097/MNH.0000000000000422.
• [6] Prognostic roles of MAGE family members in breast cancer based on KM-Plotter Data.Oncol Lett. 2019 Oct;18(4):3501-3516. doi: 10.3892/ol.2019.10722. Epub 2019 Aug 6.
• [7] The Expression of Melanoma-Associated Antigen D2 Both in Surgically Resected and Serum Samples Serves as Clinically Relevant Biomarker of Gastric Cancer Progression.Ann Surg Oncol. 2016 Feb;23 Suppl 2:S214-21. doi: 10.1245/s10434-015-4457-8. Epub 2015 Mar 6.
• [8] Nephrogenic diabetes insipidus.Curr Opin Pediatr. 2017 Apr;29(2):199-205. doi: 10.1097/MOP.0000000000000473.
• [9] Network-based approach to identify biomarkers predicting response and prognosis for HER2-negative breast cancer treatment with taxane-anthracycline neoadjuvant chemotherapy.PeerJ. 2019 Sep 3;7:e7515. doi: 10.7717/peerj.7515. eCollection 2019.
• [10] Predicting neuroendocrine tumor (carcinoid) neoplasia using gene expression profiling and supervised machine learning.Cancer. 2009 Apr 15;115(8):1638-50. doi: 10.1002/cncr.24180.
• [11] MAGE genes in the kidney: identification of MAGED2 as upregulated during kidney injury and in stressed tubular cells.Nephrol Dial Transplant. 2019 Sep 1;34(9):1498-1507. doi: 10.1093/ndt/gfy367.
• [12] Utility of molecular genetic signatures in the delineation of gastric neoplasia.Cancer. 2006 Apr 1;106(7):1480-8. doi: 10.1002/cncr.21758.
• [13] The melanoma-associated antigen MAGE-D2 suppresses TRAIL receptor 2 and protects against TRAIL-induced apoptosis in human melanoma cells.Carcinogenesis. 2012 Oct;33(10):1871-81. doi: 10.1093/carcin/bgs236. Epub 2012 Jul 12.
• [14] The role of genetic markers--NAP1L1, MAGE-D2, and MTA1--in defining small-intestinal carcinoid neoplasia.Ann Surg Oncol. 2006 Feb;13(2):253-62. doi: 10.1245/ASO.2006.12.011. Epub 2006 Jan 20.
• [15] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [16] 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.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [20] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [21] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [27] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [28] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.
• [29] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.