Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6OD55E)

• DOT Name: Epidermal growth factor receptor kinase substrate 8-like protein 2 (EPS8L2)
• Synonyms: EPS8-like protein 2; Epidermal growth factor receptor pathway substrate 8-related protein 2; EPS8-related protein 2
• Gene Name: EPS8L2
• Related Disease:
  Hearing loss, autosomal recessive 106
  Nonsyndromic genetic hearing loss
  Hearing loss, autosomal recessive
• UniProt ID: ES8L2_HUMAN
• PDB ID: 1WWU; 1WXB
• Pfam ID: PF08416 ; PF18016 ; PF00018
• Sequence:
  MSQSGAVSCCPGATNGSLGRSDGVAKMSPKDLFEQRKKYSNSNVIMHETSQYHVQHLATF
  IMDKSEAITSVDDAIRKLVQLSSKEKIWTQEMLLQVNDQSLRLLDIESQEELEDFPLPTV
  QRSQTVLNQLRYPSVLLLVCQDSEQSKPDVHFFHCDEVEAELVHEDIESALADCRLGKKM
  RPQTLKGHQEKIRQRQSILPPPQGPAPIPFQHRGGDSPEAKNRVGPQVPLSEPGFRRRES
  QEEPRAVLAQKIEKETQILNCALDDIEWFVARLQKAAEAFKQLNQRKKGKKKGKKAPAEG
  VLTLRARPPSEGEFIDCFQKIKLAINLLAKLQKHIQNPSAAELVHFLFGPLDLIVNTCSG
  PDIARSVSCPLLSRDAVDFLRGHLVPKEMSLWESLGESWMRPRSEWPREPQVPLYVPKFH
  SGWEPPVDVLQEAPWEVEGLASAPIEEVSPVSRQSIRNSQKHSPTSEPTPPGDALPPVSS
  PHTHRGYQPTPAMAKYVKILYDFTARNANELSVLKDEVLEVLEDGRQWWKLRSRSGQAGY
  VPCNILGEARPEDAGAPFEQAGQKYWGPASPTHKLPPSFPGNKDELMQHMDEVNDELIRK
  ISNIRAQPQRHFRVERSQPVSQPLTYESGPDEVRAWLEAKAFSPRIVENLGILTGPQLFS
  LNKEELKKVCGEEGVRVYSQLTMQKAFLEKQQSGSELEELMNKFHSMNQRRGEDS
• Function: Stimulates guanine exchange activity of SOS1. May play a role in membrane ruffling and remodeling of the actin cytoskeleton. In the cochlea, is required for stereocilia maintenance in adult hair cells.
• Tissue Specificity: Detected in fibroblasts and placenta.
• Reactome Pathway:
  Sensory processing of sound by outer hair cells of the cochlea (R-HSA-9662361)
  Sensory processing of sound by inner hair cells of the cochlea (R-HSA-9662360)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hearing loss, autosomal recessive 106	DIS9OAZJ	Strong	Autosomal recessive	[1]
Nonsyndromic genetic hearing loss	DISZX61P	Moderate	Autosomal recessive	[2]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Epidermal growth factor receptor kinase substrate 8-like protein 2 (EPS8L2).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Epidermal growth factor receptor kinase substrate 8-like protein 2 (EPS8L2).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Epidermal growth factor receptor kinase substrate 8-like protein 2 (EPS8L2).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Epidermal growth factor receptor kinase substrate 8-like protein 2 (EPS8L2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Epidermal growth factor receptor kinase substrate 8-like protein 2 (EPS8L2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Epidermal growth factor receptor kinase substrate 8-like protein 2 (EPS8L2).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Epidermal growth factor receptor kinase substrate 8-like protein 2 (EPS8L2).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Epidermal growth factor receptor kinase substrate 8-like protein 2 (EPS8L2).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Epidermal growth factor receptor kinase substrate 8-like protein 2 (EPS8L2).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Epidermal growth factor receptor kinase substrate 8-like protein 2 (EPS8L2).	[10]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Epidermal growth factor receptor kinase substrate 8-like protein 2 (EPS8L2).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Epidermal growth factor receptor kinase substrate 8-like protein 2 (EPS8L2).	[13]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Epidermal growth factor receptor kinase substrate 8-like protein 2 (EPS8L2).	[14]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Epidermal growth factor receptor kinase substrate 8-like protein 2 (EPS8L2).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Epidermal growth factor receptor kinase substrate 8-like protein 2 (EPS8L2).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Epidermal growth factor receptor kinase substrate 8-like protein 2 (EPS8L2).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Epidermal growth factor receptor kinase substrate 8-like protein 2 (EPS8L2).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Epidermal growth factor receptor kinase substrate 8-like protein 2 (EPS8L2).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Epidermal growth factor receptor kinase substrate 8-like protein 2 (EPS8L2).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Epidermal growth factor receptor kinase substrate 8-like protein 2 (EPS8L2).	[21]

References

• [1] EPS8L2 is a new causal gene for childhood onset autosomal recessive progressive hearing loss. Orphanet J Rare Dis. 2015 Aug 19;10:96. doi: 10.1186/s13023-015-0316-8.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] 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.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] 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.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [13] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [14] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [18] 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.
• [19] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [20] 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.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.