Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTG0W9R)

• DOT Name: Enhancer of polycomb homolog 2 (EPC2)
• Synonyms: EPC-like
• Gene Name: EPC2
• Related Disease:
  Acute myelogenous leukaemia
  Adenocarcinoma
  Alzheimer disease
  Barrett esophagus
  Eosinophilic esophagitis
  Esophageal adenocarcinoma
  Esophageal squamous cell carcinoma
  Familial multiple trichoepithelioma
  leukaemia
  Leukemia
  Schizophrenia
  Non-insulin dependent diabetes
• UniProt ID: EPC2_HUMAN
• Pfam ID: PF06752 ; PF10513
• Sequence:
  MSKLSFRARALDAAKPLPIYRGKDMPDLNDCVSINRAVPQMPTGMEKEEESEHHLQRAIS
  AQQVFREKKESMVIPVPEAESNVNYYNRLYKGEFKQPKQFIHIQPFNLDNEQPDYDMDSE
  DETLLNRLNRKMEIKPLQFEIMIDRLEKASSNQLVTLQEAKLLLNEDDYLIKAVYDYWVR
  KRKNCRGPSLIPQIKQEKRDGSTNNDPYVAFRRRTEKMQTRKNRKNDEASYEKMLKLRRE
  FSRAITILEMIKRREKTKRELLHLTLEVVEKRYHLGDYGGEILNEVKISRSEKELYATPA
  TLHNGNHHKVQECKTKHPHHLSLKEEASDVVRQKKKYPKKPKAEALITSQQPTPETLPVI
  NKSDIKQYDFHSSDEDEFPQVLSPVSEPEEENDPDGPCAFRRRAGCQYYAPRLDQANHSC
  ENSELADLDKLRYRHCLTTLTVPRRCIGFARRRIGRGGRVIMDRISTEHDPVLKQIDPEM
  LNSFSSSSQTIDFSSNFSRTNASSKHCENRLSLSEILSNIRSCRLQCFQPRLLNLQDSDS
  EECTSRKPGQTVNNKRVSAASVALLNTSKNGISVTGGITEEQFQTHQQQLVQMQRQQLAQ
  LQQKQQSQHSSQQTHPKAQGSSTSDCMSKTLDSASAHFAASAVVSAPVPSRSEVAKEQNT
  GHNNINGVVQPSGTSKTLYSTNMALSSSPGISAVQLVRTVGHTTTNHLIPALCTSSPQTL
  PMNNSCLTNAVHLNNVSVVSPVNVHINTRTSAPSPTALKLATVAASMDRVPKVTPSSAIS
  SIARENHEPERLGLNGIAETTVAMEVT
• Function: May play a role in transcription or DNA repair.
• KEGG Pathway: ATP-dependent chromatin remodeling (hsa03082)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Genetic Variation	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Barrett esophagus	DIS416Y7	Strong	Biomarker	[4]
Eosinophilic esophagitis	DISR8WSB	Strong	Biomarker	[5]
Esophageal adenocarcinoma	DISODWFP	Strong	Genetic Variation	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[7]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Biomarker	[6]
leukaemia	DISS7D1V	Strong	Biomarker	[1]
Leukemia	DISNAKFL	Strong	Biomarker	[1]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[8]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[9]

12 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 Enhancer of polycomb homolog 2 (EPC2).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Enhancer of polycomb homolog 2 (EPC2).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Enhancer of polycomb homolog 2 (EPC2).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Enhancer of polycomb homolog 2 (EPC2).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Enhancer of polycomb homolog 2 (EPC2).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Enhancer of polycomb homolog 2 (EPC2).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Enhancer of polycomb homolog 2 (EPC2).	[14]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Enhancer of polycomb homolog 2 (EPC2).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Enhancer of polycomb homolog 2 (EPC2).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Enhancer of polycomb homolog 2 (EPC2).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Enhancer of polycomb homolog 2 (EPC2).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Enhancer of polycomb homolog 2 (EPC2).	[23]

3 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 Enhancer of polycomb homolog 2 (EPC2).	[13]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Enhancer of polycomb homolog 2 (EPC2).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Enhancer of polycomb homolog 2 (EPC2).	[21]

References

• [1] Enhancers of Polycomb EPC1 and EPC2 sustain the oncogenic potential of MLL leukemia stem cells.Leukemia. 2014 May;28(5):1081-91. doi: 10.1038/leu.2013.316. Epub 2013 Oct 29.
• [2] Wnt/-Catenin Signaling Activation beyond Robust Nuclear -Catenin Accumulation in Nondysplastic Barrett's Esophagus: Regulation via Dickkopf-1.Neoplasia. 2015 Jul;17(7):598-611. doi: 10.1016/j.neo.2015.07.006.
• [3] Genome-wide association study of CSF biomarkers Abeta1-42, t-tau, and p-tau181p in the ADNI cohort.Neurology. 2011 Jan 4;76(1):69-79. doi: 10.1212/WNL.0b013e318204a397. Epub 2010 Dec 1.
• [4] Response to TNF- Is Increasing Along with the Progression in Barrett's Esophagus.Dig Dis Sci. 2017 Dec;62(12):3391-3401. doi: 10.1007/s10620-017-4821-6. Epub 2017 Oct 30.
• [5] Identification of anoctamin 1 (ANO1) as a key driver of esophageal epithelial proliferation in eosinophilic esophagitis.J Allergy Clin Immunol. 2020 Jan;145(1):239-254.e2. doi: 10.1016/j.jaci.2019.07.049. Epub 2019 Oct 21.
• [6] In-depth characterization of the Wnt-signaling/-catenin pathway in an in vitro model of Barrett's sequence.BMC Gastroenterol. 2019 Mar 6;19(1):38. doi: 10.1186/s12876-019-0957-5.
• [7] Distinct effects of EGFR inhibitors on epithelial- and mesenchymal-like esophageal squamous cell carcinoma cells.J Exp Clin Cancer Res. 2017 Aug 1;36(1):101. doi: 10.1186/s13046-017-0572-7.
• [8] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [9] Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population.Nat Genet. 2019 Mar;51(3):379-386. doi: 10.1038/s41588-018-0332-4. Epub 2019 Feb 4.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] 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.
• [20] 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.
• [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] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [23] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.