Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTLB216)

• DOT Name: MAX gene-associated protein (MGA)
• Synonyms: MAX dimerization protein 5
• Gene Name: MGA
• Related Disease:
  Neoplasm
  Barth syndrome
  Breast cancer
  Breast carcinoma
  Cardiomyopathy
  Childhood acute lymphoblastic leukemia
  Malignant soft tissue neoplasm
  Non-small-cell lung cancer
  Prostate cancer
  Prostate neoplasm
  Rheumatic heart disease
  Sarcoma
  Small lymphocytic lymphoma
  Small-cell lung cancer
  T-cell lymphoma
  Advanced cancer
  Gastrointestinal stromal tumour
• UniProt ID: MGAP_HUMAN
• Pfam ID: PF00010 ; PF16059 ; PF00907
• Sequence:
  MEEKQQIILANQDGGTVAGAAPTFFVILKQPGNGKTDQGILVTNQDACALASSVSSPVKS
  KGKICLPADCTVGGITVTLDNNSMWNEFYHRSTEMILTKQGRRMFPYCRYWITGLDSNLK
  YILVMDISPVDNHRYKWNGRWWEPSGKAEPHVLGRVFIHPESPSTGHYWMHQPVSFYKLK
  LTNNTLDQEGHIILHSMHRYLPRLHLVPAEKAVEVIQLNGPGVHTFTFPQTEFFAVTAYQ
  NIQITQLKIDYNPFAKGFRDDGLNNKPQRDGKQKNSSDQEGNNISSSSGHRVRLTEGQGS
  EIQPGDLDPLSRGHETSGKGLEKTSLNIKRDFLGFMDTDSALSEVPQLKQEISECLIASS
  FEDDSRVASPLDQNGSFNVVIKEEPLDDYDYELGECPEGVTVKQEETDEETDVYSNSDDD
  PILEKQLKRHNKVDNPEADHLSSKWLPSSPSGVAKAKMFKLDTGKMPVVYLEPCAVTRST
  VKISELPDNMLSTSRKDKSSMLAELEYLPTYIENSNETAFCLGKESENGLRKHSPDLRVV
  QKYPLLKEPQWKYPDISDSISTERILDDSKDSVGDSLSGKEDLGRKRTTMLKIATAAKVV
  NANQNASPNVPGKRGRPRKLKLCKAGRPPKNTGKSLISTKNTPVSPGSTFPDVKPDLEDV
  DGVLFVSFESKEALDIHAVDGTTEESSSLQASTTNDSGYRARISQLEKELIEDLKTLRHK
  QVIHPGLQEVGLKLNSVDPTMSIDLKYLGVQLPLAPATSFPFWNLTGTNPASPDAGFPFV
  SRTGKTNDFTKIKGWRGKFHSASASRNEGGNSESSLKNRSAFCSDKLDEYLENEGKLMET
  SMGFSSNAPTSPVVYQLPTKSTSYVRTLDSVLKKQSTISPSTSYSLKPHSVPPVSRKAKS
  QNRQATFSGRTKSSYKSILPYPVSPKQKYSHVILGDKVTKNSSGIISENQANNFVVPTLD
  ENIFPKQISLRQAQQQQQQQQGSRPPGLSKSQVKLMDLEDCALWEGKPRTYITEERADVS
  LTTLLTAQASLKTKPIHTIIRKRAPPCNNDFCRLGCVCSSLALEKRQPAHCRRPDCMFGC
  TCLKRKVVLVKGGSKTKHFQRKAAHRDPVFYDTLGEEAREEEEGIREEEEQLKEKKKRKK
  LEYTICETEPEQPVRHYPLWVKVEGEVDPEPVYIPTPSVIEPMKPLLLPQPEVLSPTVKG
  KLLTGIKSPRSYTPKPNPVIREEDKDPVYLYFESMMTCARVRVYERKKEDQRQPSSSSSP
  SPSFQQQTSCHSSPENHNNAKEPDSEQQPLKQLTCDLEDDSDKLQEKSWKSSCNEGESSS
  TSYMHQRSPGGPTKLIEIISDCNWEEDRNKILSILSQHINSNMPQSLKVGSFIIELASQR
  KSRGEKNPPVYSSRVKISMPSCQDQDDMAEKSGSETPDGPLSPGKMEDISPVQTDALDSV
  RERLHGGKGLPFYAGLSPAGKLVAYKRKPSSSTSGLIQVASNAKVAASRKPRTLLPSTSN
  SKMASSSGTATNRPGKNLKAFVPAKRPIAARPSPGGVFTQFVMSKVGALQQKIPGVSTPQ
  TLAGTQKFSIRPSPVMVVTPVVSSEPVQVCSPVTAAVTTTTPQVFLENTTAVTPMTAISD
  VETKETTYSSGATTTGVVEVSETNTSTSVTSTQSTATVNLTKTTGITTPVASVAFPKSLV
  ASPSTITLPVASTASTSLVVVTAAASSSMVTTPTSSLGSVPIILSGINGSPPVSQRPENA
  AQIPVATPQVSPNTVKRAGPRLLLIPVQQGSPTLRPVSNTQLQGHRMVLQPVRSPSGMNL
  FRHPNGQIVQLLPLHQLRGSNTQPNLQPVMFRNPGSVMGIRLPAPSKPSETPPSSTSSSA
  FSVMNPVIQAVGSSSAVNVITQAPSLLSSGASFVSQAGTLTLRISPPEPQSFASKTGSET
  KITYSSGGQPVGTASLIPLQSGSFALLQLPGQKPVPSSILQHVASLQMKRESQNPDQKDE
  TNSIKREQETKKVLQSEGEAVDPEANVIKQNSGAATSEETLNDSLEDRGDHLDEECLPEE
  GCATVKPSEHSCITGSHTDQDYKDVNEEYGARNRKSSKEKVAVLEVRTISEKASNKTVQN
  LSKVQHQKLGDVKVEQQKGFDNPEENSSEFPVTFKEESKFELSGSKVMEQQSNLQPEAKE
  KECGDSLEKDRERWRKHLKGPLTRKCVGASQECKKEADEQLIKETKTCQENSDVFQQEQG
  ISDLLGKSGITEDARVLKTECDSWSRISNPSAFSIVPRRAAKSSRGNGHFQGHLLLPGEQ
  IQPKQEKKGGRSSADFTVLDLEEDDEDDNEKTDDSIDEIVDVVSDYQSEEVDDVEKNNCV
  EYIEDDEEHVDIETVEELSEEINVAHLKTTAAHTQSFKQPSCTHISADEKAAERSRKAPP
  IPLKLKPDYWSDKLQKEAEAFAYYRRTHTANERRRRGEMRDLFEKLKITLGLLHSSKVSK
  SLILTRAFSEIQGLTDQADKLIGQKNLLTRKRNILIRKVSSLSGKTEEVVLKKLEYIYAK
  QQALEAQKRKKKMGSDEFDISPRISKQQEGSSASSVDLGQMFINNRRGKPLILSRKKDQA
  TENTSPLNTPHTSANLVMTPQGQLLTLKGPLFSGPVVAVSPDLLESDLKPQVAGSAVALP
  ENDDLFMMPRIVNVTSLATEGGLVDMGGSKYPHEVPDSKPSDHLKDTVRNEDNSLEDKGR
  ISSRGNRDGRVTLGPTQVFLANKDSGYPQIVDVSNMQKAQEFLPKKISGDMRGIQYKWKE
  SESRGERVKSKDSSFHKLKMKDLKDSSIEMELRKVTSAIEEAALDSSELLTNMEDEDDTD
  ETLTSLLNEIAFLNQQLNDDSVGLAELPSSMDTEFPGDARRAFISKVPPGSRATFQVEHL
  GTGLKELPDVQGESDSISPLLLHLEDDDFSENEKQLAEPASEPDVLKIVIDSEIKDSLLS
  NKKAIDGGKNTSGLPAEPESVSSPPTLHMKTGLENSNSTDTLWRPMPKLAPLGLKVANPS
  SDADGQSLKVMPCLAPIAAKVGSVGHKMNLTGNDQEGRESKVMPTLAPVVAKLGNSGASP
  SSAGK
• Function: Functions as a dual-specificity transcription factor, regulating the expression of both MAX-network and T-box family target genes. Functions as a repressor or an activator. Binds to 5'-AATTTCACACCTAGGTGTGAAATT-3' core sequence and seems to regulate MYC-MAX target genes. Suppresses transcriptional activation by MYC and inhibits MYC-dependent cell transformation. Function activated by heterodimerization with MAX. This heterodimerization serves the dual function of both generating an E-box-binding heterodimer and simultaneously blocking interaction of a corepressor.
• KEGG Pathway: Polycomb repressive complex (hsa03083)
• Reactome Pathway: Transcriptional Regulation by E2F6 (R-HSA-8953750)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Barth syndrome	DISDI4KU	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[2]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[4]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Genetic Variation	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[6]
Prostate cancer	DISF190Y	Strong	Biomarker	[7]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[7]
Rheumatic heart disease	DISCI8JQ	Strong	Biomarker	[8]
Sarcoma	DISZDG3U	Strong	Genetic Variation	[5]
Small lymphocytic lymphoma	DIS30POX	Strong	Genetic Variation	[9]
Small-cell lung cancer	DISK3LZD	Strong	Altered Expression	[6]
T-cell lymphoma	DISSXRTQ	Strong	Biomarker	[10]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[11]
Gastrointestinal stromal tumour	DIS6TJYS	Limited	Genetic Variation	[12]

7 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 MAX gene-associated protein (MGA).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of MAX gene-associated protein (MGA).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of MAX gene-associated protein (MGA).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of MAX gene-associated protein (MGA).	[16]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of MAX gene-associated protein (MGA).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of MAX gene-associated protein (MGA).	[23]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of MAX gene-associated protein (MGA).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of MAX gene-associated protein (MGA).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of MAX gene-associated protein (MGA).	[19]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of MAX gene-associated protein (MGA).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of MAX gene-associated protein (MGA).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of MAX gene-associated protein (MGA).	[22]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of MAX gene-associated protein (MGA).	[21]

References

• [1] Comparative analysis of co-occurring mutations of specific tumor suppressor genes in lung adenocarcinoma between Asian and Caucasian populations.J Cancer Res Clin Oncol. 2019 Mar;145(3):747-757. doi: 10.1007/s00432-018-02828-5. Epub 2019 Jan 23.
• [2] Delayed appearance of 3-methylglutaconic aciduria in neonates with early onset metabolic cardiomyopathies: A potential pitfall for the diagnosis.Am J Med Genet A. 2020 Jan;182(1):64-70. doi: 10.1002/ajmg.a.61383. Epub 2019 Nov 15.
• [3] Detection of mammaglogin A in blood from breast cancer patients, before and after treatment, using a one-tube nested PCR protocol. Association with the absence of tumor estrogen receptors.Clin Biochem. 2011 Dec;44(17-18):1429-33. doi: 10.1016/j.clinbiochem.2011.08.1140. Epub 2011 Sep 12.
• [4] RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia.Nat Genet. 2014 Feb;46(2):116-25. doi: 10.1038/ng.2874. Epub 2014 Jan 12.
• [5] Sarcoma with MGA-NUTM1 fusion in the lung: an emerging entity.Virchows Arch. 2020 Feb;476(2):317-322. doi: 10.1007/s00428-019-02623-8. Epub 2019 Aug 5.
• [6] MAX inactivation in small cell lung cancer disrupts MYC-SWI/SNF programs and is synthetic lethal with BRG1.Cancer Discov. 2014 Mar;4(3):292-303. doi: 10.1158/2159-8290.CD-13-0799. Epub 2013 Dec 20.
• [7] The long tail of oncogenic drivers in prostate cancer.Nat Genet. 2018 May;50(5):645-651. doi: 10.1038/s41588-018-0078-z. Epub 2018 Apr 2.
• [8] mga genosensor for early detection of human rheumatic heart disease.Appl Biochem Biotechnol. 2014 May;173(1):228-38. doi: 10.1007/s12010-014-0836-z. Epub 2014 Mar 18.
• [9] A cloning and expression system to probe T-cell receptor specificity and assess functional avidity to neoantigens.Blood. 2018 Nov 1;132(18):1911-1921. doi: 10.1182/blood-2018-04-843763. Epub 2018 Aug 27.
• [10] Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma.Nat Genet. 2015 Sep;47(9):1061-6. doi: 10.1038/ng.3358. Epub 2015 Jul 20.
• [11] Analysis of head and neck carcinoma progression reveals novel and relevant stage-specific changes associated with immortalisation and malignancy.Sci Rep. 2019 Aug 19;9(1):11992. doi: 10.1038/s41598-019-48229-7.
• [12] Genetic alterations in cell cycle regulation-associated genes may promote primary progression of gastrointestinal stromal tumors.Lab Invest. 2020 Mar;100(3):426-437. doi: 10.1038/s41374-019-0322-x. Epub 2019 Sep 30.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] 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.
• [15] 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.
• [16] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [17] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [24] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.