Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB9VQFA)

• DOT Name: Eomesodermin homolog (EOMES)
• Synonyms: T-box brain protein 2; T-brain-2; TBR-2
• Gene Name: EOMES
• Related Disease:
  Acute myelogenous leukaemia
  Colonic neoplasm
  Rheumatoid arthritis
  Advanced cancer
  Alzheimer disease
  Anxiety disorder
  Arthrogryposis
  Autoimmune disease
  Autoimmune lymphoproliferative syndrome type 1
  Bladder cancer
  Clear cell renal carcinoma
  Colon cancer
  Colorectal carcinoma
  Cytomegalovirus infection
  Digestive system neuroendocrine tumor, grade 1/2
  Dilated cardiomyopathy 1A
  Helminth infection
  Hepatocellular carcinoma
  Immunodeficiency 14
  Inflammatory bowel disease
  Isolated congenital microcephaly
  Laryngeal squamous cell carcinoma
  Myelodysplastic syndrome
  Neoplasm
  Nervous system inflammation
  Non-small-cell lung cancer
  Promyelocytic leukaemia
  Renal cell carcinoma
  Seminoma
  Systemic lupus erythematosus
  Urinary bladder cancer
  Urinary bladder neoplasm
  Microcephaly-polymicrogyria-corpus callosum agenesis syndrome
  Extranodal NK/T-cell Lymphoma
  Autoimmune disorder of the nervous system
  Hashimoto thyroiditis
• UniProt ID: EOMES_HUMAN
• Pfam ID: PF00907 ; PF16176
• Sequence:
  MQLGEQLLVSSVNLPGAHFYPLESARGGSGGSAGHLPSAAPSPQKLDLDKASKKFSGSLS
  CEAVSGEPAAASAGAPAAMLSDTDAGDAFASAAAVAKPGPPDGRKGSPCGEEELPSAAAA
  AAAAAAAAAATARYSMDSLSSERYYLQSPGPQGSELAAPCSLFPYQAAAGAPHGPVYPAP
  NGARYPYGSMLPPGGFPAAVCPPGRAQFGPGAGAGSGAGGSSGGGGGPGTYQYSQGAPLY
  GPYPGAAAAGSCGGLGGLGVPGSGFRAHVYLCNRPLWLKFHRHQTEMIITKQGRRMFPFL
  SFNINGLNPTAHYNVFVEVVLADPNHWRFQGGKWVTCGKADNNMQGNKMYVHPESPNTGS
  HWMRQEISFGKLKLTNNKGANNNNTQMIVLQSLHKYQPRLHIVEVTEDGVEDLNEPSKTQ
  TFTFSETQFIAVTAYQNTDITQLKIDHNPFAKGFRDNYDSSHQIVPGGRYGVQSFFPEPF
  VNTLPQARYYNGERTVPQTNGLLSPQQSEEVANPPQRWLVTPVQQPGTNKLDISSYESEY
  TSSTLLPYGIKSLPLQTSHALGYYPDPTFPAMAGWGGRGSYQRKMAAGLPWTSRTSPTVF
  SEDQLSKEKVKEEIGSSWIETPPSIKSLDSNDSGVYTSACKRRRLSPSNSSNENSPSIKC
  EDINAEEYSKDTSKGMGGYYAFYTTP
• Function: Functions as a transcriptional activator playing a crucial role during development. Functions in trophoblast differentiation and later in gastrulation, regulating both mesoderm delamination and endoderm specification. Plays a role in brain development being required for the specification and the proliferation of the intermediate progenitor cells and their progeny in the cerebral cortex. Also involved in the differentiation of CD8+ T-cells during immune response regulating the expression of lytic effector genes.
• Tissue Specificity: Expressed in CD8+ T-cells.
• Reactome Pathway:
  Germ layer formation at gastrulation (R-HSA-9754189)
  Epithelial-Mesenchymal Transition (EMT) during gastrulation (R-HSA-9758919)
  Formation of definitive endoderm (R-HSA-9823730)
  Specification of primordial germ cells (R-HSA-9827857)
  Cardiogenesis (R-HSA-9733709)

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Biomarker	[1]
Colonic neoplasm	DISSZ04P	Definitive	Biomarker	[2]
Rheumatoid arthritis	DISTSB4J	Definitive	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[4]
Anxiety disorder	DISBI2BT	Strong	Biomarker	[5]
Arthrogryposis	DISC81CM	Strong	Biomarker	[6]
Autoimmune disease	DISORMTM	Strong	Altered Expression	[7]
Autoimmune lymphoproliferative syndrome type 1	DISAFGRA	Strong	Biomarker	[8]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[9]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[10]
Colon cancer	DISVC52G	Strong	Altered Expression	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[2]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[11]
Digestive system neuroendocrine tumor, grade 1/2	DISDR98B	Strong	Biomarker	[12]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Biomarker	[6]
Helminth infection	DIS7CGKY	Strong	Biomarker	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[14]
Immunodeficiency 14	DISI1EMU	Strong	Altered Expression	[15]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[16]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[17]
Laryngeal squamous cell carcinoma	DIS9UUVF	Strong	Posttranslational Modification	[18]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[19]
Neoplasm	DISZKGEW	Strong	Altered Expression	[20]
Nervous system inflammation	DISB3X5A	Strong	Altered Expression	[21]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[22]
Promyelocytic leukaemia	DISYGG13	Strong	Altered Expression	[23]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[10]
Seminoma	DIS3J8LJ	Strong	Biomarker	[24]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[25]
Urinary bladder cancer	DISDV4T7	moderate	Biomarker	[26]
Urinary bladder neoplasm	DIS7HACE	moderate	Biomarker	[26]
Microcephaly-polymicrogyria-corpus callosum agenesis syndrome	DIS8Q6SX	Supportive	Autosomal recessive	[27]
Extranodal NK/T-cell Lymphoma	DIS72GCL	Disputed	Altered Expression	[28]
Autoimmune disorder of the nervous system	DIS7OIK6	Limited	Biomarker	[29]
Hashimoto thyroiditis	DIS77CDF	Limited	Altered Expression	[30]

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 Eomesodermin homolog (EOMES).	[31]
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of Eomesodermin homolog (EOMES).	[32]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Eomesodermin homolog (EOMES).	[33]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Eomesodermin homolog (EOMES).	[34]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Eomesodermin homolog (EOMES).	[36]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Eomesodermin homolog (EOMES).	[37]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Eomesodermin homolog (EOMES).	[38]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Eomesodermin homolog (EOMES).	[39]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Eomesodermin homolog (EOMES).	[40]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Eomesodermin homolog (EOMES).	[41]
Phenytoin	DMNOKBV	Approved	Phenytoin increases the expression of Eomesodermin homolog (EOMES).	[42]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Eomesodermin homolog (EOMES).	[44]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Eomesodermin homolog (EOMES).	[41]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Eomesodermin homolog (EOMES).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Eomesodermin homolog (EOMES).	[43]

References

• [1] Eomes(+)T-bet(low) CD8(+) T Cells Are Functionally Impaired and Are Associated with Poor Clinical Outcome in Patients with Acute Myeloid Leukemia.Cancer Res. 2019 Apr 1;79(7):1635-1645. doi: 10.1158/0008-5472.CAN-18-3107. Epub 2019 Feb 1.
• [2] Reciprocal regulation of BMF and BIRC5 (Survivin) linked to Eomes overexpression in colorectal cancer.Cancer Lett. 2016 Oct 28;381(2):341-8. doi: 10.1016/j.canlet.2016.08.008. Epub 2016 Aug 15.
• [3] EOMES-positive CD4(+) Tcells are increased in PTPN22 (1858T) risk allele carriers.Eur J Immunol. 2018 Apr;48(4):655-669. doi: 10.1002/eji.201747296. Epub 2018 Feb 28.
• [4] Linking Genetics of Brain Changes to Alzheimer's Disease: Sparse Whole Genome Association Scan of Regional MRI Volumes in the ADNI and AddNeuroMed Cohorts.J Alzheimers Dis. 2015;45(3):851-64. doi: 10.3233/JAD-142214.
• [5] Ablation of hippocampal neurogenesis in mice impairs the response to stress during the dark cycle.Nat Commun. 2015 Sep 29;6:8373. doi: 10.1038/ncomms9373.
• [6] Expression of functional T-cell markers and T-cell receptor Vbeta repertoire in endomyocardial biopsies from patients presenting with acute myocarditis and dilated cardiomyopathy.Eur J Heart Fail. 2011 Jun;13(6):611-8. doi: 10.1093/eurjhf/hfr014. Epub 2011 Mar 19.
• [7] The autoimmune disease-associated transcription factors EOMES and TBX21 are dysregulated in multiple sclerosis and define a molecular subtype of disease.Clin Immunol. 2014 Mar;151(1):16-24. doi: 10.1016/j.clim.2014.01.003. Epub 2014 Jan 15.
• [8] Cutting edge: Lymphoproliferation caused by Fas deficiency is dependent on the transcription factor eomesodermin.J Immunol. 2010 Dec 15;185(12):7151-5. doi: 10.4049/jimmunol.1003193. Epub 2010 Nov 12.
• [9] Diagnosis of bladder cancer recurrence based on urinary levels of EOMES, HOXA9, POU4F2, TWIST1, VIM, and ZNF154 hypermethylation.PLoS One. 2012;7(10):e46297. doi: 10.1371/journal.pone.0046297. Epub 2012 Oct 3.
• [10] Genomic profiling identifies alterations in TGFbeta signaling through loss of TGFbeta receptor expression in human renal cell carcinogenesis and progression.Oncogene. 2003 Sep 11;22(39):8053-62. doi: 10.1038/sj.onc.1206835.
• [11] Cutting Edge: Divergent Requirement of T-Box Transcription Factors in Effector and Memory NK Cells.J Immunol. 2018 Mar 15;200(6):1977-1981. doi: 10.4049/jimmunol.1700416. Epub 2018 Feb 9.
• [12] A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors.Nat Genet. 2018 Jul;50(7):979-989. doi: 10.1038/s41588-018-0138-4. Epub 2018 Jun 18.
• [13] Assessing the role of the T-box transcription factor Eomes in B cell differentiation during either Th1 or Th2 cell-biased responses.PLoS One. 2018 Dec 6;13(12):e0208343. doi: 10.1371/journal.pone.0208343. eCollection 2018.
• [14] Integrated analyses of DNA methylation and hydroxymethylation reveal tumor suppressive roles of ECM1, ATF5, and EOMES in human hepatocellular carcinoma.Genome Biol. 2014 Dec 3;15(12):533. doi: 10.1186/s13059-014-0533-9.
• [15] CD57 identifies T cells with functional senescence before terminal differentiation and relative telomere shortening in patients with activated PI3 kinase delta syndrome.Immunol Cell Biol. 2018 Nov;96(10):1060-1071. doi: 10.1111/imcb.12169. Epub 2018 Jun 14.
• [16] Eomesodermin controls a unique differentiation program in human IL-10 and IFN- coproducing regulatory Tcells.Eur J Immunol. 2019 Jan;49(1):96-111. doi: 10.1002/eji.201847722. Epub 2018 Nov 29.
• [17] Genomic selection identifies vertebrate transcription factor Fezf2 binding sites and target genes.J Biol Chem. 2011 May 27;286(21):18641-9. doi: 10.1074/jbc.M111.236471. Epub 2011 Apr 6.
• [18] High frequency of TGF-beta-receptor-II mutations in microdissected tissue samples from laryngeal squamous cell carcinomas.Lab Invest. 2003 Aug;83(8):1241-51. doi: 10.1097/01.lab.0000081389.98880.79.
• [19] CD8(+) T cells exhaustion induced by myeloid-derived suppressor cells in myelodysplastic syndromes patients might be through TIM3/Gal-9 pathway.J Cell Mol Med. 2020 Jan;24(1):1046-1058. doi: 10.1111/jcmm.14825. Epub 2019 Nov 22.
• [20] Eomesodermin Increases Survival and IL-2 Responsiveness of Tumor-specific CD8+ T Cells in an Adoptive Transfer Model of Cancer Immunotherapy.J Immunother. 2018 Feb/Mar;41(2):53-63. doi: 10.1097/CJI.0000000000000206.
• [21] Eomes-expressing T-helper cells as potential target of therapy in chronic neuroinflammation.Neurochem Int. 2019 Nov;130:104348. doi: 10.1016/j.neuint.2018.11.023. Epub 2018 Dec 1.
• [22] Function of Human Tumor-Infiltrating Lymphocytes in Early-Stage Non-Small Cell Lung Cancer.Cancer Immunol Res. 2019 Jun;7(6):896-909. doi: 10.1158/2326-6066.CIR-18-0713. Epub 2019 May 3.
• [23] CD4(hi)CD8(low) Double-Positive T Cells Are Associated with Graft Rejection in a Nonhuman Primate Model of Islet Transplantation.J Immunol Res. 2018 Jul 10;2018:3861079. doi: 10.1155/2018/3861079. eCollection 2018.
• [24] In vivo differentiation and genomic evolution in adult male germ cell tumors.Genes Chromosomes Cancer. 2008 Jan;47(1):43-55. doi: 10.1002/gcc.20504.
• [25] Higher activation of the interferon-gamma signaling pathway in systemic lupus erythematosus patients with a high type I IFN score: relation to disease activity.Clin Rheumatol. 2018 Oct;37(10):2675-2684. doi: 10.1007/s10067-018-4138-7. Epub 2018 May 17.
• [26] Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer. Chem Res Toxicol. 2015 Jun 15;28(6):1144-55. doi: 10.1021/tx500393y. Epub 2015 Jun 3.
• [27] Homozygous silencing of T-box transcription factor EOMES leads to microcephaly with polymicrogyria and corpus callosum agenesis. Nat Genet. 2007 Apr;39(4):454-6. doi: 10.1038/ng1993. Epub 2007 Mar 11.
• [28] Transcription factors engaged in development of NK cells are commonly expressed in nasal NK/T-cell lymphomas.Hum Pathol. 2011 Sep;42(9):1319-28. doi: 10.1016/j.humpath.2009.11.022. Epub 2011 Feb 16.
• [29] Foxo3 Transcription Factor Drives Pathogenic THelper 1 Differentiation by Inducing the Expression of Eomes.Immunity. 2016 Oct 18;45(4):774-787. doi: 10.1016/j.immuni.2016.09.010. Epub 2016 Oct 11.
• [30] Association of increased eomesodermin, BCL6, and granzyme B expression with major clinical manifestations of Hashimoto's thyroiditis - an observational study.Immunol Invest. 2018 Apr;47(3):279-292. doi: 10.1080/08820139.2018.1423571. Epub 2018 Jan 10.
• [31] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [32] Molecular characterization of a toxicological tipping point during human stem cell differentiation. Reprod Toxicol. 2020 Jan;91:1-13. doi: 10.1016/j.reprotox.2019.10.001. Epub 2019 Oct 7.
• [33] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [34] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [35] Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer. Chem Res Toxicol. 2015 Jun 15;28(6):1144-55. doi: 10.1021/tx500393y. Epub 2015 Jun 3.
• [36] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [37] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [38] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [39] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [40] Neuronal and cardiac toxicity of pharmacological compounds identified through transcriptomic analysis of human pluripotent stem cell-derived embryoid bodies. Toxicol Appl Pharmacol. 2021 Dec 15;433:115792. doi: 10.1016/j.taap.2021.115792. Epub 2021 Nov 3.
• [41] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [42] Role of phenytoin in wound healing: microarray analysis of early transcriptional responses in human dermal fibroblasts. Biochem Biophys Res Commun. 2004 Feb 13;314(3):661-6. doi: 10.1016/j.bbrc.2003.12.146.
• [43] 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.
• [44] Inhibition of Super-Enhancer Activity in Autoinflammatory Site-Derived T Cells Reduces Disease-Associated Gene Expression. Cell Rep. 2015 Sep 29;12(12):1986-96. doi: 10.1016/j.celrep.2015.08.046. Epub 2015 Sep 17.