Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPAU0L4)

• DOT Name: Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (ARFGEF1)
• Synonyms: Brefeldin A-inhibited GEP 1; ADP-ribosylation factor guanine nucleotide-exchange factor 1; p200 ARF guanine nucleotide exchange factor; p200 ARF-GEP1
• Gene Name: ARFGEF1
• Related Disease:
  Developmental delay, impaired speech, and behavioral abnormalities, with or without seizures
  Invasive breast carcinoma
  Joubert syndrome 21
  Advanced cancer
  Atrioventricular block
  Autism spectrum disorder
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Epilepsy
  Hepatitis
  Hepatitis A virus infection
  LennoxGastaut syndrome
  Neoplasm
  Obsessive compulsive disorder
  rubella
  Thyroid gland papillary carcinoma
  Adult glioblastoma
  Glioblastoma multiforme
  Parkinson disease
  Cutaneous mastocytosis
  Glaucoma/ocular hypertension
  Psychotic disorder
  Schizophrenia
• UniProt ID: BIG1_HUMAN
• PDB ID: 3LTL; 5EE5; 5J5C
• Pfam ID: PF20252 ; PF16213 ; PF01369 ; PF09324 ; PF12783
• Sequence:
  MYEGKKTKNMFLTRALEKILADKEVKKAHHSQLRKACEVALEEIKAETEKQSPPHGEAKA
  GSSTLPPVKSKTNFIEADKYFLPFELACQSKCPRIVSTSLDCLQKLIAYGHLTGNAPDST
  TPGKKLIDRIIETICGCFQGPQTDEGVQLQIIKALLTAVTSQHIEIHEGTVLQAVRTCYN
  IYLASKNLINQTTAKATLTQMLNVIFARMENQALQEAKQMEKERHRQHHHLLQSPVSHHE
  PESPQLRYLPPQTVDHISQEHEGDLDLHTNDVDKSLQDDTEPENGSDISSAENEQTEADQ
  ATAAETLSKNEVLYDGENHDCEEKPQDIVQNIVEEMVNIVVGDMGEGTTINASADGNIGT
  IEDGSDSENIQANGIPGTPISVAYTPSLPDDRLSVSSNDTQESGNSSGPSPGAKFSHILQ
  KDAFLVFRSLCKLSMKPLSDGPPDPKSHELRSKILSLQLLLSILQNAGPIFRTNEMFINA
  IKQYLCVALSKNGVSSVPEVFELSLSIFLTLLSNFKTHLKMQIEVFFKEIFLYILETSTS
  SFDHKWMVIQTLTRICADAQSVVDIYVNYDCDLNAANIFERLVNDLSKIAQGRGSQELGM
  SNVQELSLRKKGLECLVSILKCMVEWSKDQYVNPNSQTTLGQEKPSEQEMSEIKHPETIN
  RYGSLNSLESTSSSGIGSYSTQMSGTDNPEQFEVLKQQKEIIEQGIDLFNKKPKRGIQYL
  QEQGMLGTTPEDIAQFLHQEERLDSTQVGEFLGDNDKFNKEVMYAYVDQHDFSGKDFVSA
  LRMFLEGFRLPGEAQKIDRLMEKFAARYLECNQGQTLFASADTAYVLAYSIIMLTTDLHS
  PQVKNKMTKEQYIKMNRGINDSKDLPEEYLSAIYNEIAGKKISMKETKELTIPTKSSKQN
  VASEKQRRLLYNLEMEQMAKTAKALMEAVSHVQAPFTSATHLEHVRPMFKLAWTPFLAAF
  SVGLQDCDDTEVASLCLEGIRCAIRIACIFSIQLERDAYVQALARFTLLTVSSGITEMKQ
  KNIDTIKTLITVAHTDGNYLGNSWHEILKCISQLELAQLIGTGVKPRYISGTVRGREGSL
  TGTKDQAPDEFVGLGLVGGNVDWKQIASIQESIGETSSQSVVVAVDRIFTGSTRLDGNAI
  VDFVRWLCAVSMDELLSTTHPRMFSLQKIVEISYYNMGRIRLQWSRIWEVIGDHFNKVGC
  NPNEDVAIFAVDSLRQLSMKFLEKGELANFRFQKDFLRPFEHIMKRNRSPTIRDMVVRCI
  AQMVNSQAANIRSGWKNIFSVFHLAASDQDESIVELAFQTTGHIVTLVFEKHFPATIDSF
  QDAVKCLSEFACNAAFPDTSMEAIRLIRHCAKYVSDRPQAFKEYTSDDMNVAPEDRVWVR
  GWFPILFELSCIINRCKLDVRTRGLTVMFEIMKTYGHTYEKHWWQDLFRIVFRIFDNMKL
  PEQQTEKAEWMTTTCNHALYAICDVFTQYLEVLSDVLLDDIFAQLYWCVQQDNEQLARSG
  TNCLENVVILNGEKFTLEIWDKTCNCTLDIFKTTIPHALLTWRPNSGETAPPPPSPVSEK
  PLDTISQKSVDIHDSIQPRSVDNRPQAPLVSASAVNEEVSKIKSTAKFPEQKLFAALLIK
  CVVQLELIQTIDNIVFFPATSKKEDAENLAAAQRDAVDFDVRVDTQDQGMYRFLTSQQLF
  KLLDCLLESHRFAKAFNSNNEQRTALWKAGFKGKSKPNLLKQETSSLACGLRILFRMYMD
  ESRVSAWEEVQQRLLNVCSEALSYFLTLTSESHREAWTNLLLLFLTKVLKISDNRFKAHA
  SFYYPLLCEIMQFDLIPELRAVLRRFFLRIGVVFQISQPPEQELGINKQ
• Function: Promotes guanine-nucleotide exchange on ARF1 and ARF3. Promotes the activation of ARF1/ARF3 through replacement of GDP with GTP. Involved in vesicular trafficking. Required for the maintenance of Golgi structure; the function may be independent of its GEF activity. Required for the maturaion of integrin beta-1 in the Golgi. Involved in the establishment and persistence of cell polarity during directed cell movement in wound healing. Proposed to act as A kinase-anchoring protein (AKAP) and may mediate crosstalk between Arf and PKA pathways. Inhibits GAP activity of MYO9B probably through competitive RhoA binding. The function in the nucleus remains to be determined.
• Tissue Specificity: Expressed in placenta, lung, heart, brain, kidney and pancreas.
• KEGG Pathway: Endocytosis (hsa04144)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental delay, impaired speech, and behavioral abnormalities, with or without seizures	DISMSPUE	Definitive	Autosomal dominant	[1]
Invasive breast carcinoma	DISANYTW	Definitive	Biomarker	[2]
Joubert syndrome 21	DIS6DGTX	Definitive	CausalMutation	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Atrioventricular block	DIS8YLE6	Strong	Biomarker	[5]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[8]
Epilepsy	DISBB28L	Strong	Biomarker	[1]
Hepatitis	DISXXX35	Strong	Altered Expression	[9]
Hepatitis A virus infection	DISUMFQV	Strong	Altered Expression	[9]
LennoxGastaut syndrome	DISOTGO5	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Obsessive compulsive disorder	DIS1ZMM2	Strong	Biomarker	[11]
rubella	DISXUI9P	Strong	Biomarker	[12]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Biomarker	[13]
Adult glioblastoma	DISVP4LU	Disputed	Altered Expression	[14]
Glioblastoma multiforme	DISK8246	Disputed	Altered Expression	[14]
Parkinson disease	DISQVHKL	Disputed	Biomarker	[15]
Cutaneous mastocytosis	DISLBZEF	Limited	Biomarker	[16]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Biomarker	[17]
Psychotic disorder	DIS4UQOT	Limited	Biomarker	[18]
Schizophrenia	DISSRV2N	Limited	Unknown	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (ARFGEF1) increases the response to substance of Cisplatin.	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (ARFGEF1).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (ARFGEF1).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (ARFGEF1).	[22]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (ARFGEF1).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (ARFGEF1).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (ARFGEF1).	[27]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (ARFGEF1).	[28]
ORG2058	DMH1M6N	Investigative	ORG2058 decreases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (ARFGEF1).	[29]

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 Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (ARFGEF1).	[24]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (ARFGEF1).	[26]

References

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• [2] Cholesterol, Cholesterol-Lowering Medication Use, and Breast Cancer Outcome in the BIG 1-98 Study.J Clin Oncol. 2017 Apr 10;35(11):1179-1188. doi: 10.1200/JCO.2016.70.3116. Epub 2017 Feb 13.
• [3] Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity.J Med Genet. 2015 Aug;52(8):514-22. doi: 10.1136/jmedgenet-2015-103087. Epub 2015 Jun 19.
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• [5] Ro/SSA autoantibodies directly bind cardiomyocytes, disturb calcium homeostasis, and mediate congenital heart block.J Exp Med. 2005 Jan 3;201(1):11-7. doi: 10.1084/jem.20041859.
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• [10] RNA-Seq analysis of interferon inducible p204-mediated network in anti-tumor immunity.Sci Rep. 2018 Apr 24;8(1):6495. doi: 10.1038/s41598-018-24561-2.
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• [17] Ex-PRESS implantation for different types of glaucoma.Int J Ophthalmol. 2019 Aug 18;12(8):1290-1297. doi: 10.18240/ijo.2019.08.09. eCollection 2019.
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• [21] 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.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch Toxicol. 2012 Apr;86(4):571-89.
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• [30] Genome-wide local ancestry approach identifies genes and variants associated with chemotherapeutic susceptibility in African Americans. PLoS One. 2011;6(7):e21920. doi: 10.1371/journal.pone.0021920. Epub 2011 Jul 6.