Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM3CQZT)

• DOT Name: Brefeldin A-inhibited guanine nucleotide-exchange protein 2 (ARFGEF2)
• Synonyms: Brefeldin A-inhibited GEP 2; ADP-ribosylation factor guanine nucleotide-exchange factor 2
• Gene Name: ARFGEF2
• Related Disease:
  Alcohol dependence
  Breast cancer
  Breast carcinoma
  Cardiomyopathy
  Dystonia
  Huntington disease
  Movement disorder
  Obsessive compulsive disorder
  Periventricular heterotopia with microcephaly, autosomal recessive
  West syndrome
  Neuroblastoma
  Periventricular nodular heterotopia
  Adult glioblastoma
  Glioblastoma multiforme
  Paroxysmal nocturnal haemoglobinuria
• UniProt ID: BIG2_HUMAN
• PDB ID: 3L8N; 3SWV
• Pfam ID: PF20252 ; PF16213 ; PF01369 ; PF09324 ; PF12783
• Sequence:
  MQESQTKSMFVSRALEKILADKEVKRPQHSQLRRACQVALDEIKAEIEKQRLGTAAPPKA
  NFIEADKYFLPFELACQSKSPRVVSTSLDCLQKLIAYGHITGNAPDSGAPGKRLIDRIVE
  TICSCFQGPQTDEGVQLQIIKALLTAVTSPHIEIHEGTILQTVRTCYNIYLASKNLINQT
  TAKATLTQMLNVIFTRMENQVLQEARELEKPIQSKPQSPVIQAAAVSPKFVRLKHSQAQS
  KPTTPEKTDLTNGEHARSDSGKVSTENGDAPRERGSSLSGTDDGAQEVVKDILEDVVTSA
  IKEAAEKHGLTEPERVLGELECQECAIPPGVDENSQTNGIADDRQSLSSADNLESDAQGH
  QVAARFSHVLQKDAFLVFRSLCKLSMKPLGEGPPDPKSHELRSKVVSLQLLLSVLQNAGP
  VFRTHEMFINAIKQYLCVALSKNGVSSVPDVFELSLAIFLTLLSNFKMHLKMQIEVFFKE
  IFLNILETSTSSFEHRWMVIQTLTRICADAQCVVDIYVNYDCDLNAANIFERLVNDLSKI
  AQGRSGHELGMTPLQELSLRKKGLECLVSILKCMVEWSKDLYVNPNHQTSLGQERLTDQE
  IGDGKGLDMARRCSVTSMESTVSSGTQTTVQDDPEQFEVIKQQKEIIEHGIELFNKKPKR
  GIQFLQEQGMLGTSVEDIAQFLHQEERLDSTQVGDFLGDSARFNKEVMYAYVDQLDFCEK
  EFVSALRTFLEGFRLPGEAQKIDRLMEKFAARYIECNQGQTLFASADTAYVLAYSIIMLT
  TDLHSPQVKNKMTKEQYIKMNRGINDSKDLPEEYLSSIYEEIEGKKIAMKETKELTIATK
  STKQNVASEKQRRLLYNLEMEQMAKTAKALMEAVSHAKAPFTSATHLDHVRPMFKLVWTP
  LLAAYSIGLQNCDDTEVASLCLEGIRCAIRIACIFGMQLERDAYVQALARFSLLTASSSI
  TEMKQKNIDTIKTLITVAHTDGNYLGNSWHEILKCISQLELAQLIGTGVKTRYLSGSGRE
  REGSLKGHTLAGEEFMGLGLGNLVSGGVDKRQMASFQESVGETSSQSVVVAVDRIFTGST
  RLDGNAIVDFVRWLCAVSMDELASPHHPRMFSLQKIVEISYYNMNRIRLQWSRIWHVIGD
  HFNKVGCNPNEDVAIFAVDSLRQLSMKFLEKGELANFRFQKDFLRPFEHIMKKNRSPTIR
  DMAIRCIAQMVNSQAANIRSGWKNIFAVFHQAASDHDGNIVELAFQTTCHIVTTIFQHHF
  PAAIDSFQDAVKCLSEFACNAAFPDTSMEAIRLIRFCGKYVSERPRVLQEYTSDDMNVAP
  GDRVWVRGWFPILFELSCIINRCKLDVRTRGLTVMFEIMKSYGHTFEKHWWQDLFRIVFR
  IFDNMKLPEQLSEKSEWMTTTCNHALYAICDVFTQFYEALNEVLLSDVFAQLQWCVKQDN
  EQLARSGTNCLENLVISNGEKFSPEVWDETCNCMLDIFKTTIPHVLLTWRPVGMEEDSSE
  KHLDVDLDRQSLSSIDKNPSERGQSQLSNPTDDSWKGRPYANQKLFASLLIKCVVQLELI
  QTIDNIVFYPATSKKEDAEHMVAAQQDTLDADIHIETEDQGMYKYMSSQHLFKLLDCLQE
  SHSFSKAFNSNYEQRTVLWRAGFKGKSKPNLLKQETSSLACCLRILFRMYVDENRRDSWE
  EIQQRLLTVCSEALAYFITVNSESHREAWTSLLLLLLTKTLKINDEKFKAHASMYYPYLC
  EIMQFDLIPELRAVLRKFFLRIGVVYKIWIPEEPSQVPAALSPVW
• Function: Promotes guanine-nucleotide exchange on ARF1 and ARF3 and to a lower extent on ARF5 and ARF6. Promotes the activation of ARF1/ARF5/ARF6 through replacement of GDP with GTP. Involved in the regulation of Golgi vesicular transport. Required for the integrity of the endosomal compartment. Involved in trafficking from the trans-Golgi network (TGN) to endosomes and is required for membrane association of the AP-1 complex and GGA1. Seems to be involved in recycling of the transferrin receptor from recycling endosomes to the plasma membrane. Probably is involved in the exit of GABA(A) receptors from the endoplasmic reticulum. Involved in constitutive release of tumor necrosis factor receptor 1 via exosome-like vesicles; the function seems to involve PKA and specifically PRKAR2B. Proposed to act as A kinase-anchoring protein (AKAP) and may mediate crosstalk between Arf and PKA pathways.
• Tissue Specificity: Expressed in placenta, lung, heart, brain, kidney and pancreas.
• KEGG Pathway: Endocytosis (hsa04144)
• Reactome Pathway: Association of TriC/CCT with target proteins during biosynthesis (R-HSA-390471)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alcohol dependence	DIS4ZSCO	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[3]
Dystonia	DISJLFGW	Strong	Genetic Variation	[4]
Huntington disease	DISQPLA4	Strong	Altered Expression	[5]
Movement disorder	DISOJJ2D	Strong	Genetic Variation	[3]
Obsessive compulsive disorder	DIS1ZMM2	Strong	Biomarker	[6]
Periventricular heterotopia with microcephaly, autosomal recessive	DISVEINW	Strong	Autosomal recessive	[7]
West syndrome	DISLIAU9	Strong	Genetic Variation	[8]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[9]
Periventricular nodular heterotopia	DISU3ZRI	Supportive	Autosomal dominant	[10]
Adult glioblastoma	DISVP4LU	Disputed	Altered Expression	[11]
Glioblastoma multiforme	DISK8246	Disputed	Altered Expression	[11]
Paroxysmal nocturnal haemoglobinuria	DISBHMYH	Limited	Genetic Variation	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 2 (ARFGEF2).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 2 (ARFGEF2).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 2 (ARFGEF2).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 2 (ARFGEF2).	[16]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 2 (ARFGEF2).	[18]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 2 (ARFGEF2).	[18]
Clodronate	DM9Y6X7	Approved	Clodronate affects the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 2 (ARFGEF2).	[18]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 2 (ARFGEF2).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 2 (ARFGEF2).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 2 (ARFGEF2).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 2 (ARFGEF2).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 2 (ARFGEF2).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Brefeldin A-inhibited guanine nucleotide-exchange protein 2 (ARFGEF2).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Brefeldin A-inhibited guanine nucleotide-exchange protein 2 (ARFGEF2).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Brefeldin A-inhibited guanine nucleotide-exchange protein 2 (ARFGEF2).	[17]

References

• [1] Genome-wide association study in bipolar patients stratified by co-morbidity.PLoS One. 2011;6(12):e28477. doi: 10.1371/journal.pone.0028477. Epub 2011 Dec 21.
• [2] Pregnancies during and after trastuzumab and/or lapatinib in patients with human epidermal growth factor receptor 2-positive early breast cancer: Analysis from the NeoALTTO (BIG 1-06) and ALTTO (BIG 2-06) trials.Cancer. 2019 Jan 15;125(2):307-316. doi: 10.1002/cncr.31784. Epub 2018 Oct 18.
• [3] The expanding phenotypic spectrum of ARFGEF2 gene mutation: Cardiomyopathy and movement disorder.Brain Dev. 2016 Jan;38(1):124-7. doi: 10.1016/j.braindev.2015.06.004. Epub 2015 Jun 28.
• [4] Periventricular nodular heterotopia and dystonia due to an ARFGEF2 mutation.Pediatr Neurol. 2014 Sep;51(3):461-4. doi: 10.1016/j.pediatrneurol.2014.05.008. Epub 2014 May 15.
• [5] ADP-ribosylation factor guanine nucleotide-exchange factor 2 (ARFGEF2): a new potential biomarker in Huntington's disease.J Int Med Res. 2010 Sep-Oct;38(5):1653-62. doi: 10.1177/147323001003800510.
• [6] Attenuation of compulsive-like behavior by fluvoxamine in a non-induced mouse model of obsessive-compulsive disorder.Behav Pharmacol. 2018 Jun;29(4):299-305. doi: 10.1097/FBP.0000000000000348.
• [7] 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.
• [8] West syndrome, microcephaly, grey matter heterotopia and hypoplasia of corpus callosum due to a novel ARFGEF2 mutation.J Med Genet. 2013 Nov;50(11):772-5. doi: 10.1136/jmedgenet-2013-101752. Epub 2013 Jun 28.
• [9] Overlapping expression of ARFGEF2 and Filamin A in the neuroependymal lining of the lateral ventricles: insights into the cause of periventricular heterotopia.J Comp Neurol. 2006 Jan 20;494(3):476-84. doi: 10.1002/cne.20806.
• [10] Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex. Nat Genet. 2004 Jan;36(1):69-76. doi: 10.1038/ng1276. Epub 2003 Nov 30.
• [11] Involvement of BIG1 and BIG2 in regulating VEGF expression and angiogenesis.FASEB J. 2019 Sep;33(9):9959-9973. doi: 10.1096/fj.201900342RR. Epub 2019 Jun 14.
• [12] Multiple genomic copy number variants associated with periventricular nodular heterotopia indicate extreme genetic heterogeneity.Eur J Hum Genet. 2019 Jun;27(6):909-918. doi: 10.1038/s41431-019-0335-3. Epub 2019 Jan 25.
• [13] 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.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] 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.
• [17] 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.
• [18] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [19] 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.
• [20] Exposure to environmental bisphenol A inhibits HTR-8/SVneo cell migration and invasion. J Biomed Res. 2020 Jun 30;34(5):369-378. doi: 10.7555/JBR.34.20200013.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.