Details of Drug Off-Target (DOT)

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

• DOT Name: Max dimerization protein 4 (MXD4)
• Synonyms: Max dimerizer 4; Class C basic helix-loop-helix protein 12; bHLHc12; Max-associated protein 4; Max-interacting transcriptional repressor MAD4
• Gene Name: MXD4
• Related Disease:
  Glioblastoma multiforme
  Neoplasm
  Progressive multifocal leukoencephalopathy
• UniProt ID: MAD4_HUMAN
• Pfam ID: PF00010
• Sequence:
  MELNSLLILLEAAEYLERRDREAEHGYASVLPFDGDFAREKTKAAGLVRKAPNNRSSHNE
  LEKHRRAKLRLYLEQLKQLVPLGPDSTRHTTLSLLKRAKVHIKKLEEQDRRALSIKEQLQ
  QEHRFLKRRLEQLSVQSVERVRTDSTGSAVSTDDSEQEVDIEGMEFGPGELDSVGSSSDA
  DDHYSLQSGTGGDSGFGPHCRRLGRPALS
• Function: Transcriptional repressor. Binds with MAX to form a sequence-specific DNA-binding protein complex which recognizes the core sequence 5'-CAC[GA]TG-3'. Antagonizes MYC transcriptional activity by competing for MAX and suppresses MYC dependent cell transformation.
• Reactome Pathway: Nuclear signaling by ERBB4 (R-HSA-1251985)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Progressive multifocal leukoencephalopathy	DISX02WS	Strong	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Max dimerization protein 4 (MXD4).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Max dimerization protein 4 (MXD4).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Max dimerization protein 4 (MXD4).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Max dimerization protein 4 (MXD4).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Max dimerization protein 4 (MXD4).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Max dimerization protein 4 (MXD4).	[8]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Max dimerization protein 4 (MXD4).	[9]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Max dimerization protein 4 (MXD4).	[10]
Palbociclib	DMD7L94	Approved	Palbociclib increases the expression of Max dimerization protein 4 (MXD4).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Max dimerization protein 4 (MXD4).	[12]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Max dimerization protein 4 (MXD4).	[7]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Max dimerization protein 4 (MXD4).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Max dimerization protein 4 (MXD4).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Max dimerization protein 4 (MXD4).	[7]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Max dimerization protein 4 (MXD4).	[16]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Max dimerization protein 4 (MXD4).	[17]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Max dimerization protein 4 (MXD4).	[18]

References

• [1] Dissecting the complex regulation of Mad4 in glioblastoma multiforme cells.Cancer Biol Ther. 2012 Nov;13(13):1339-48. doi: 10.4161/cbt.21814. Epub 2012 Aug 16.
• [2] Novel MXD4-NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma.Genes Chromosomes Cancer. 2018 Nov;57(11):557-563. doi: 10.1002/gcc.22668.
• [3] Detection of JC virus DNA in peripheral lymphocytes from patients with and without progressive multifocal leukoencephalopathy.Ann Neurol. 1992 Apr;31(4):454-62. doi: 10.1002/ana.410310426.
• [4] 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.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [8] 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.
• [9] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [10] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [11] Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012 Oct;11(10):2138-48. doi: 10.1158/1535-7163.MCT-12-0562. Epub 2012 Aug 6.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [14] 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.
• [15] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [16] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [17] 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.
• [18] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.