Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3M8WEU)

• DOT Name: Eukaryotic translation initiation factor 4E-binding protein 2 (EIF4EBP2)
• Synonyms: 4E-BP2; eIF4E-binding protein 2
• Gene Name: EIF4EBP2
• UniProt ID: 4EBP2_HUMAN
• PDB ID: 2MX4; 3AM7
• Pfam ID: PF05456
• Sequence:
  MSSSAGSGHQPSQSRAIPTRTVAISDAAQLPHDYCTTPGGTLFSTTPGGTRIIYDRKFLL
  DRRNSPMAQTPPCHLPNIPGVTSPGTLIEDSKVEVNNLNNLNNHDRKHAVGDDAQFEMDI
• Function: Repressor of translation initiation involved in synaptic plasticity, learning and memory formation. Regulates EIF4E activity by preventing its assembly into the eIF4F complex: hypophosphorylated form of EIF4EBP2 competes with EIF4G1/EIF4G3 and strongly binds to EIF4E, leading to repress translation. In contrast, hyperphosphorylated form dissociates from EIF4E, allowing interaction between EIF4G1/EIF4G3 and EIF4E, leading to initiation of translation. EIF4EBP2 is enriched in brain and acts as a regulator of synapse activity and neuronal stem cell renewal via its ability to repress translation initiation. Mediates the regulation of protein translation by hormones, growth factors and other stimuli that signal through the MAP kinase and mTORC1 pathways.
• KEGG Pathway: Longevity regulating pathway - multiple species (hsa04213)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Eukaryotic translation initiation factor 4E-binding protein 2 (EIF4EBP2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Eukaryotic translation initiation factor 4E-binding protein 2 (EIF4EBP2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Eukaryotic translation initiation factor 4E-binding protein 2 (EIF4EBP2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Eukaryotic translation initiation factor 4E-binding protein 2 (EIF4EBP2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Eukaryotic translation initiation factor 4E-binding protein 2 (EIF4EBP2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Eukaryotic translation initiation factor 4E-binding protein 2 (EIF4EBP2).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Eukaryotic translation initiation factor 4E-binding protein 2 (EIF4EBP2).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Eukaryotic translation initiation factor 4E-binding protein 2 (EIF4EBP2).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Eukaryotic translation initiation factor 4E-binding protein 2 (EIF4EBP2).	[9]
Marinol	DM70IK5	Approved	Marinol increases the expression of Eukaryotic translation initiation factor 4E-binding protein 2 (EIF4EBP2).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Eukaryotic translation initiation factor 4E-binding protein 2 (EIF4EBP2).	[3]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Eukaryotic translation initiation factor 4E-binding protein 2 (EIF4EBP2).	[11]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Eukaryotic translation initiation factor 4E-binding protein 2 (EIF4EBP2).	[3]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of Eukaryotic translation initiation factor 4E-binding protein 2 (EIF4EBP2).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Eukaryotic translation initiation factor 4E-binding protein 2 (EIF4EBP2).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Eukaryotic translation initiation factor 4E-binding protein 2 (EIF4EBP2).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Eukaryotic translation initiation factor 4E-binding protein 2 (EIF4EBP2).	[16]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Eukaryotic translation initiation factor 4E-binding protein 2 (EIF4EBP2).	[18]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid decreases the expression of Eukaryotic translation initiation factor 4E-binding protein 2 (EIF4EBP2).	[3]

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 decreases the methylation of Eukaryotic translation initiation factor 4E-binding protein 2 (EIF4EBP2).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Eukaryotic translation initiation factor 4E-binding protein 2 (EIF4EBP2).	[17]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [8] Inhibition of fatty acid synthase expression by 1alpha,25-dihydroxyvitamin D3 in prostate cancer cells. J Steroid Biochem Mol Biol. 2003 May;85(1):1-8. doi: 10.1016/s0960-0760(03)00142-0.
• [9] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [10] 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.
• [11] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [12] Effects of metformin and pioglitazone combination on apoptosis and AMPK/mTOR signaling pathway in human anaplastic thyroid cancer cells. J Biochem Mol Toxicol. 2020 Oct;34(10):e22547. doi: 10.1002/jbt.22547. Epub 2020 Jun 26.
• [13] 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.
• [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] BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia. Blood Cancer J. 2013 Jul 19;3(7):e126. doi: 10.1038/bcj.2013.24.
• [16] 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.
• [17] 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.
• [18] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.