Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7XYA2T)

• DOT Name: Epidermal growth factor receptor kinase substrate 8-like protein 3 (EPS8L3)
• Synonyms: EPS8-like protein 3; Epidermal growth factor receptor pathway substrate 8-related protein 3; EPS8-related protein 3
• Gene Name: EPS8L3
• Related Disease:
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Familial multiple trichoepithelioma
  Hepatocellular carcinoma
  Prostate cancer
  Prostate neoplasm
  Marie Unna hereditary hypotrichosis
  Prostate carcinoma
• UniProt ID: ES8L3_HUMAN
• PDB ID: 1WXT
• Pfam ID: PF08416 ; PF18016 ; PF00018
• Sequence:
  MSRPSSRAIYLHRKEYSQNLTSEPTLLQHRVEHLMTCKQGSQRVQGPEDALQKLFEMDAQ
  GRVWSQDLILQVRDGWLQLLDIETKEELDSYRLDSIQAMNVALNTCSYNSILSITVQEPG
  LPGTSTLLFQCQEVGAERLKTSLQKALEEELEQRPRLGGLQPGQDRWRGPAMERPLPMEQ
  ARYLEPGIPPEQPHQRTLEHSLPPSPRPLPRHTSAREPSAFTLPPPRRSSSPEDPERDEE
  VLNHVLRDIELFMGKLEKAQAKTSRKKKFGKKNKDQGGLTQAQYIDCFQKIKHSFNLLGR
  LATWLKETSAPELVHILFKSLNFILARCPEAGLAAQVISPLLTPKAINLLQSCLSPPESN
  LWMGLGPAWTTSRADWTGDEPLPYQPTFSDDWQLPEPSSQAPLGYQDPVSLRRGSHRLGS
  TSHFPQEKTHNHDPQPGDPNSRPSSPKPAQPALKMQVLYEFEARNPRELTVVQGEKLEVL
  DHSKRWWLVKNEAGRSGYIPSNILEPLQPGTPGTQGQSPSRVPMLRLSSRPEEVTDWLQA
  ENFSTATVRTLGSLTGSQLLRIRPGELQMLCPQEAPRILSRLEAVRRMLGISP

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Definitive	Biomarker	[1]
Liver cancer	DISDE4BI	Definitive	Biomarker	[1]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[4]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[4]
Marie Unna hereditary hypotrichosis	DISYE5SW	Supportive	Autosomal dominant	[5]
Prostate carcinoma	DISMJPLE	Limited	Genetic Variation	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	Epidermal growth factor receptor kinase substrate 8-like protein 3 (EPS8L3) affects the response to substance of 2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE.	[4]

7 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 Epidermal growth factor receptor kinase substrate 8-like protein 3 (EPS8L3).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Epidermal growth factor receptor kinase substrate 8-like protein 3 (EPS8L3).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Epidermal growth factor receptor kinase substrate 8-like protein 3 (EPS8L3).	[8]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Epidermal growth factor receptor kinase substrate 8-like protein 3 (EPS8L3).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Epidermal growth factor receptor kinase substrate 8-like protein 3 (EPS8L3).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Epidermal growth factor receptor kinase substrate 8-like protein 3 (EPS8L3).	[12]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE increases the expression of Epidermal growth factor receptor kinase substrate 8-like protein 3 (EPS8L3).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Epidermal growth factor receptor kinase substrate 8-like protein 3 (EPS8L3).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Epidermal growth factor receptor kinase substrate 8-like protein 3 (EPS8L3).	[13]

References

• [1] Upregulation of EPS8L3 is associated with tumorigenesis and poor prognosis in patients with liver cancer.Mol Med Rep. 2019 Sep;20(3):2493-2499. doi: 10.3892/mmr.2019.10471. Epub 2019 Jul 4.
• [2] Marie Unna hereditary hypotrichosis accompanied by multiple familial trichoepithelioma in a Chinese family.J Dermatol. 2019 May;46(5):413-417. doi: 10.1111/1346-8138.14811. Epub 2019 Feb 27.
• [3] Overexpression of EPS8L3 promotes cell proliferation by inhibiting the transactivity of FOXO1 in HCC.Neoplasma. 2018 Sep 19;65(5):701-707. doi: 10.4149/neo_2018_170725N503. Epub 2018 Jun 17.
• [4] Xenobiotic metabolizing gene variants, dietary heterocyclic amine intake, and risk of prostate cancer. Cancer Res. 2009 Mar 1;69(5):1877-84. doi: 10.1158/0008-5472.CAN-08-2447. Epub 2009 Feb 17.
• [5] Exome sequencing identified a missense mutation of EPS8L3 in Marie Unna hereditary hypotrichosis. J Med Genet. 2012 Dec;49(12):727-30. doi: 10.1136/jmedgenet-2012-101134. Epub 2012 Oct 25.
• [6] 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.
• [7] 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.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [10] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [11] 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.
• [12] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [13] 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.
• [14] Xenobiotic metabolizing gene variants, dietary heterocyclic amine intake, and risk of prostate cancer. Cancer Res. 2009 Mar 1;69(5):1877-84. doi: 10.1158/0008-5472.CAN-08-2447. Epub 2009 Feb 17.