Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU10BSF)

• DOT Name: Protein Mdm4 (MDM4)
• Synonyms: Double minute 4 protein; Mdm2-like p53-binding protein; Protein Mdmx; p53-binding protein Mdm4
• Gene Name: MDM4
• Related Disease: Bone marrow failure syndrome 6
• UniProt ID: MDM4_HUMAN
• PDB ID: 2CR8 ; 2MWY ; 2N06 ; 2N0U ; 2N0W ; 2N14 ; 2VJE ; 2VJF ; 2VYR ; 3DAB ; 3EQY ; 3FDO ; 3FE7 ; 3FEA ; 3JZO ; 3JZP ; 3JZQ ; 3LBJ ; 3MQR ; 3U15 ; 4RXZ ; 5MNJ ; 5UML ; 5VK1 ; 6Q9Q ; 6Q9S ; 6Q9U ; 6Q9W ; 6Q9Y ; 6YR5 ; 6YR7 ; 7C3Q ; 7C3Y ; 7C44 ; 7EL4 ; 7KJN ; 7MLA ; 8HDG ; 8IA5
• Pfam ID: PF13920 ; PF00641
• Sequence:
  MTSFSTSAQCSTSDSACRISPGQINQVRPKLPLLKILHAAGAQGEMFTVKEVMHYLGQYI
  MVKQLYDQQEQHMVYCGGDLLGELLGRQSFSVKDPSPLYDMLRKNLVTLATATTDAAQTL
  ALAQDHSMDIPSQDQLKQSAEESSTSRKRTTEDDIPTLPTSEHKCIHSREDEDLIENLAQ
  DETSRLDLGFEEWDVAGLPWWFLGNLRSNYTPRSNGSTDLQTNQDVGTAIVSDTTDDLWF
  LNESVSEQLGVGIKVEAADTEQTSEEVGKVSDKKVIEVGKNDDLEDSKSLSDDTDVEVTS
  EDEWQCTECKKFNSPSKRYCFRCWALRKDWYSDCSKLTHSLSTSDITAIPEKENEGNDVP
  DCRRTISAPVVRPKDAYIKKENSKLFDPCNSVEFLDLAHSSESQETISSMGEQLDNLSEQ
  RTDTENMEDCQNLLKPCSLCEKRPRDGNIIHGRTGHLVTCFHCARRLKKAGASCPICKKE
  IQLVIKVFIA
• Function: Along with MDM2, contributes to TP53 regulation. Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions.
• Tissue Specificity: Expressed in all tissues tested with high levels in thymus.
• KEGG Pathway:
  p53 sig.ling pathway (hsa04115)
  MicroR.s in cancer (hsa05206)
• Reactome Pathway:
  Oncogene Induced Senescence (R-HSA-2559585)
  Ub-specific processing proteases (R-HSA-5689880)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  Regulation of TP53 Degradation (R-HSA-6804757)
  Regulation of TP53 Activity through Methylation (R-HSA-6804760)
  Stabilization of p53 (R-HSA-69541)
  Oxidative Stress Induced Senescence (R-HSA-2559580)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone marrow failure syndrome 6	DISXFAJ4	Limited	Autosomal dominant	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
DTI-015	DMXZRW0	Approved	Protein Mdm4 (MDM4) decreases the response to substance of DTI-015.	[21]

17 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 Protein Mdm4 (MDM4).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein Mdm4 (MDM4).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein Mdm4 (MDM4).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein Mdm4 (MDM4).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Protein Mdm4 (MDM4).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Protein Mdm4 (MDM4).	[7]
Marinol	DM70IK5	Approved	Marinol increases the expression of Protein Mdm4 (MDM4).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Protein Mdm4 (MDM4).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Protein Mdm4 (MDM4).	[10]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Protein Mdm4 (MDM4).	[11]
Daunorubicin	DMQUSBT	Approved	Daunorubicin decreases the expression of Protein Mdm4 (MDM4).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein Mdm4 (MDM4).	[13]
Rigosertib	DMOSTXF	Phase 3	Rigosertib affects the expression of Protein Mdm4 (MDM4).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Protein Mdm4 (MDM4).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein Mdm4 (MDM4).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Protein Mdm4 (MDM4).	[19]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Protein Mdm4 (MDM4).	[20]

2 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 increases the methylation of Protein Mdm4 (MDM4).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein Mdm4 (MDM4).	[18]

References

• [1] Influence of MDM2 and MDM4 on development and survival in hereditary retinoblastoma. Pediatr Blood Cancer. 2012 Jul 15;59(1):39-43. doi: 10.1002/pbc.24014. Epub 2011 Dec 16.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [6] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [7] 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.
• [8] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [9] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [10] 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.
• [11] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [12] Daunorubicin-induced variations in gene transcription: commitment to proliferation arrest, senescence and apoptosis. Biochem J. 2003 Jun 15;372(Pt 3):703-11. doi: 10.1042/BJ20021950.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res. 2012 Apr 1;18(7):1979-91. doi: 10.1158/1078-0432.CCR-11-2113. Epub 2012 Feb 20.
• [15] 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.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] 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.
• [18] 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.
• [19] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [20] p53 activation by Ni(II) is a HIF-1 independent response causing caspases 9/3-mediated apoptosis in human lung cells. Toxicol Appl Pharmacol. 2013 Jun 15;269(3):233-9. doi: 10.1016/j.taap.2013.03.023. Epub 2013 Apr 6.
• [21] HDMX regulates p53 activity and confers chemoresistance to 3-bis(2-chloroethyl)-1-nitrosourea. Neuro Oncol. 2010 Sep;12(9):956-66. doi: 10.1093/neuonc/noq045. Epub 2010 May 14.