Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIBXC1B)

• DOT Name: Early endosome antigen 1 (EEA1)
• Synonyms: Endosome-associated protein p162; Zinc finger FYVE domain-containing protein 2
• Gene Name: EEA1
• Related Disease:
  Advanced cancer
  Cyclic hematopoiesis
  Herpes simplex infection
  Lysosomal storage disease
  Type-1/2 diabetes
• UniProt ID: EEA1_HUMAN
• PDB ID: 1HYI; 1HYJ; 1JOC; 3MJH
• Pfam ID: PF01363
• Sequence:
  MLRRILQRTPGRVGSQGSDLDSSATPINTVDVNNESSSEGFICPQCMKSLGSADELFKHY
  EAVHDAGNDSGHGGESNLALKRDDVTLLRQEVQDLQASLKEEKWYSEELKKELEKYQGLQ
  QQEAKPDGLVTDSSAELQSLEQQLEEAQTENFNIKQMKDLFEQKAAQLATEIADIKSKYD
  EERSLREAAEQKVTRLTEELNKEATVIQDLKTELLQRPGIEDVAVLKKELVQVQTLMDNM
  TLERERESEKLKDECKKLQSQYASSEATISQLRSELAKGPQEVAVYVQELQKLKSSVNEL
  TQKNQTLTENLLKKEQDYTKLEEKHNEESVSKKNIQATLHQKDLDCQQLQSRLSASETSL
  HRIHVELSEKGEATQKLKEELSEVETKYQHLKAEFKQLQQQREEKEQHGLQLQSEINQLH
  SKLLETERQLGEAHGRLKEQRQLSSEKLMDKEQQVADLQLKLSRLEEQLKEKVTNSTELQ
  HQLDKTKQQHQEQQALQQSTTAKLREAQNDLEQVLRQIGDKDQKIQNLEALLQKSKENIS
  LLEKEREDLYAKIQAGEGETAVLNQLQEKNHTLQEQVTQLTEKLKNQSESHKQAQENLHD
  QVQEQKAHLRAAQDRVLSLETSVNELNSQLNESKEKVSQLDIQIKAKTELLLSAEAAKTA
  QRADLQNHLDTAQNALQDKQQELNKITTQLDQVTAKLQDKQEHCSQLESHLKEYKEKYLS
  LEQKTEELEGQIKKLEADSLEVKASKEQALQDLQQQRQLNTDLELRATELSKQLEMEKEI
  VSSTRLDLQKKSEALESIKQKLTKQEEEKKILKQDFETLSQETKIQHEELNNRIQTTVTE
  LQKVKMEKEALMTELSTVKDKLSKVSDSLKNSKSEFEKENQKGKAAILDLEKTCKELKHQ
  LQVQMENTLKEQKELKKSLEKEKEASHQLKLELNSMQEQLIQAQNTLKQNEKEEQQLQGN
  INELKQSSEQKKKQIEALQGELKIAVLQKTELENKLQQQLTQAAQELAAEKEKISVLQNN
  YEKSQETFKQLQSDFYGRESELLATRQDLKSVEEKLSLAQEDLISNRNQIGNQNKLIQEL
  KTAKATLEQDSAKKEQQLQERCKALQDIQKEKSLKEKELVNEKSKLAEIEEIKCRQEKEI
  TKLNEELKSHKLESIKEITNLKDAKQLLIQQKLELQGKADSLKAAVEQEKRNQQILKDQV
  KKEEEELKKEFIEKEAKLHSEIKEKEVGMKKHEENEAKLTMQITALNENLGTVKKEWQSS
  QRRVSELEKQTDDLRGEIAVLEATVQNNQDERRALLERCLKGEGEIEKLQTKVLELQRKL
  DNTTAAVQELGRENQSLQIKHTQALNRKWAEDNEVQNCMACGKGFSVTVRRHHCRQCGNI
  FCAECSAKNALTPSSKKPVRVCDACFNDLQG
• Function: Binds phospholipid vesicles containing phosphatidylinositol 3-phosphate and participates in endosomal trafficking.
• KEGG Pathway:
  Endocytosis (hsa04144)
  Phagosome (hsa04145)
  Tuberculosis (hsa05152)
• Reactome Pathway: Toll Like Receptor 9 (TLR9) Cascade (R-HSA-168138)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Altered Expression	[1]
Cyclic hematopoiesis	DISQQOM4	Strong	Biomarker	[2]
Herpes simplex infection	DISL1SAV	Strong	Altered Expression	[3]
Lysosomal storage disease	DIS6QM6U	Limited	Biomarker	[4]
Type-1/2 diabetes	DISIUHAP	Limited	Genetic Variation	[5]

12 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 Early endosome antigen 1 (EEA1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Early endosome antigen 1 (EEA1).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Early endosome antigen 1 (EEA1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Early endosome antigen 1 (EEA1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Early endosome antigen 1 (EEA1).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Early endosome antigen 1 (EEA1).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Early endosome antigen 1 (EEA1).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Early endosome antigen 1 (EEA1).	[15]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Early endosome antigen 1 (EEA1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Early endosome antigen 1 (EEA1).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Early endosome antigen 1 (EEA1).	[19]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Early endosome antigen 1 (EEA1).	[20]

2 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 Early endosome antigen 1 (EEA1).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Early endosome antigen 1 (EEA1).	[16]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Chloroquine	DMSI5CB	Phase 3 Trial	Chloroquine affects the localization of Early endosome antigen 1 (EEA1).	[14]

References

• [1] BPGAP1 spatially integrates JNK/ERK signaling crosstalk in oncogenesis.Oncogene. 2017 Jun 1;36(22):3178-3192. doi: 10.1038/onc.2016.466. Epub 2017 Jan 16.
• [2] Apical-to-basolateral transepithelial transport of cow's milk caseins by intestinal Caco-2 cell monolayers: MS-based quantitation of cellularly degraded - and -casein fragments.J Biochem. 2018 Aug 1;164(2):113-125. doi: 10.1093/jb/mvy034.
• [3] Misdirection of endosomal trafficking mediated by herpes simplex virus-encoded glycoprotein B.FASEB J. 2017 Apr;31(4):1650-1667. doi: 10.1096/fj.201600521R. Epub 2017 Jan 24.
• [4] Cross-regulation of defective endolysosome trafficking and enhanced autophagy through TFEB in UNC13D deficiency.Autophagy. 2019 Oct;15(10):1738-1756. doi: 10.1080/15548627.2019.1596475. Epub 2019 Apr 5.
• [5] Exome sequencing identifies a new candidate mutation for susceptibility to diabetes in a family with highly aggregated type 2 diabetes.Mol Genet Metab. 2013 May;109(1):112-7. doi: 10.1016/j.ymgme.2013.02.010. Epub 2013 Feb 21.
• [6] 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.
• [7] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [8] 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.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy. 2018;14(8):1435-1455. doi: 10.1080/15548627.2018.1474314. Epub 2018 Jul 20.
• [15] 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.
• [16] 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.
• [17] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [18] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [19] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [20] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.