Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYYQX85)

• DOT Name: ADP-ribosylation factor 3 (ARF3)
• Gene Name: ARF3
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Capillary malformation-arteriovenous malformation syndrome
  Complex neurodevelopmental disorder
  Myotonic dystrophy
  Neoplasm
  Testicular germ cell tumor
  Neuroblastoma
  Parkinson disease
• UniProt ID: ARF3_HUMAN
• PDB ID: 6II6; 8P50
• Pfam ID: PF00025
• Sequence:
  MGNIFGNLLKSLIGKKEMRILMVGLDAAGKTTILYKLKLGEIVTTIPTIGFNVETVEYKN
  ISFTVWDVGGQDKIRPLWRHYFQNTQGLIFVVDSNDRERVNEAREELMRMLAEDELRDAV
  LLVFANKQDLPNAMNAAEITDKLGLHSLRHRNWYIQATCATSGDGLYEGLDWLANQLKNK
  K
• Function: GTP-binding protein that functions as an allosteric activator of the cholera toxin catalytic subunit, an ADP-ribosyltransferase. Involved in protein trafficking; may modulate vesicle budding and uncoating within the Golgi apparatus.
• KEGG Pathway: Endocytosis (hsa04144)
• Reactome Pathway:
  COPI-mediated anterograde transport (R-HSA-6807878)
  COPI-dependent Golgi-to-ER retrograde traffic (R-HSA-6811434)
  Synthesis of PIPs at the Golgi membrane (R-HSA-1660514)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Capillary malformation-arteriovenous malformation syndrome	DISMN03Q	Strong	Genetic Variation	[3]
Complex neurodevelopmental disorder	DISB9AFI	Strong	Autosomal dominant	[4]
Myotonic dystrophy	DISNBEMX	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Testicular germ cell tumor	DIS5RN24	Strong	Biomarker	[7]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[8]
Parkinson disease	DISQVHKL	Limited	Biomarker	[9]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	ADP-ribosylation factor 3 (ARF3) affects the response to substance of Fluorouracil.	[21]
Paclitaxel	DMLB81S	Approved	ADP-ribosylation factor 3 (ARF3) affects the response to substance of Paclitaxel.	[22]

9 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 ADP-ribosylation factor 3 (ARF3).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ADP-ribosylation factor 3 (ARF3).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ADP-ribosylation factor 3 (ARF3).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of ADP-ribosylation factor 3 (ARF3).	[14]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of ADP-ribosylation factor 3 (ARF3).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of ADP-ribosylation factor 3 (ARF3).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of ADP-ribosylation factor 3 (ARF3).	[18]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of ADP-ribosylation factor 3 (ARF3).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of ADP-ribosylation factor 3 (ARF3).	[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 ADP-ribosylation factor 3 (ARF3).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of ADP-ribosylation factor 3 (ARF3).	[17]

References

• [1] Proteomics analysis of H-RAS-mediated oncogenic transformation in a genetically defined human ovarian cancer model.Oncogene. 2005 Sep 8;24(40):6174-84. doi: 10.1038/sj.onc.1208753.
• [2] Up-regulated ADP-Ribosylation factor 3 promotes breast cancer cell proliferation through the participation of FOXO1.Exp Cell Res. 2019 Nov 15;384(2):111624. doi: 10.1016/j.yexcr.2019.111624. Epub 2019 Sep 17.
• [3] RASA1 regulates the function of lymphatic vessel valves in mice.J Clin Invest. 2017 Jun 30;127(7):2569-2585. doi: 10.1172/JCI89607. Epub 2017 May 22.
• [4] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [5] The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase.EMBO J. 1996 Apr 15;15(8):1885-93.
• [6] Rab25 augments cancer cell invasiveness through a 1 integrin/EGFR/VEGF-A/Snail signaling axis and expression of fascin.Exp Mol Med. 2018 Jan 26;50(1):e435. doi: 10.1038/emm.2017.248.
• [7] Overexpression of RhoA mRNA is associated with advanced stage in testicular germ cell tumour.BJU Int. 2001 Feb;87(3):227-31. doi: 10.1046/j.1464-410x.2001.02030.x.
• [8] HaRas activates the NADPH oxidase complex in human neuroblastoma cells via extracellular signal-regulated kinase 1/2 pathway.J Neurochem. 2004 Nov;91(3):613-22. doi: 10.1111/j.1471-4159.2004.02754.x.
• [9] GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease.Biochemistry. 2007 Feb 6;46(5):1380-8. doi: 10.1021/bi061960m.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [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] Differential protein expression of peroxiredoxin I and II by benzo(a)pyrene and quercetin treatment in 22Rv1 and PrEC prostate cell lines. Toxicol Appl Pharmacol. 2007 Apr 15;220(2):197-210. doi: 10.1016/j.taap.2006.12.030. Epub 2007 Jan 9.
• [15] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [16] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [17] 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.
• [18] 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.
• [19] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [20] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [21] Mechanistic and predictive profiling of 5-Fluorouracil resistance in human cancer cells. Cancer Res. 2004 Nov 15;64(22):8167-76. doi: 10.1158/0008-5472.CAN-04-0970.
• [22] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.