Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGQV0CU)

• DOT Name: Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (ARFGEF3)
• Synonyms: ARFGEF family member 3
• Gene Name: ARFGEF3
• Related Disease:
  Breast cancer
  Breast carcinoma
  Esophageal squamous cell carcinoma
  Neoplasm
  Cardiovascular disease
  Chronic obstructive pulmonary disease
  Lung cancer
  Lung carcinoma
  Gastric cancer
  Stomach cancer
• UniProt ID: BIG3_HUMAN
• Pfam ID: PF20252 ; PF16213 ; PF09324
• Sequence:
  MEEILRKLQKEASGSKYKAIKESCTWALETLGGLDTIVKIPPHVLREKCLLPLQLALESK
  NVKLAQHALAGMQKLLSEERFVSMETDSDEKQLLNQILNAVKVTPSLNEDLQVEVMKVLL
  CITYTPTFDLNGSAVLKIAEVCIETYISSCHQRSINTAVRATLSQMLSDLTLQLRQRQEN
  TIIENPDVPQDFGNQGSTVESLCDDVVSVLTVLCEKLQAAINDSQQLQLLYLECILSVLS
  SSSSSMHLHRRFTDLIWKNLCPALIVILGNPIHDKTITSAHTSSTSTSLESDSASPGVSD
  HGRGSGCSCTAPALSGPVARTIYYIAAELVRLVGSVDSMKPVLQSLYHRVLLYPPPQHRV
  EAIKIMKEILGSPQRLCDLAGPSSTESESRKRSISKRKSHLDLLKLIMDGMTEACIKGGI
  EACYAAVSCVCTLLGALDELSQGKGLSEGQVQLLLLRLEELKDGAEWSRDSMEINEADFR
  WQRRVLSSEHTPWESGNERSLDISISVTTDTGQTTLEGELGQTTPEDHSGNHKNSLKSPA
  IPEGKETLSKVLETEAVDQPDVVQRSHTVPYPDITNFLSVDCRTRSYGSRYSESNFSVDD
  QDLSRTEFDSCDQYSMAAEKDSGRSDVSDIGSDNCSLADEEQTPRDCLGHRSLRTAALSL
  KLLKNQEADQHSARLFIQSLEGLLPRLLSLSNVEEVDTALQNFASTFCSGMMHSPGFDGN
  SSLSFQMLMNADSLYTAAHCALLLNLKLSHGDYYRKRPTLAPGVMKDFMKQVQTSGVLMV
  FSQAWIEELYHQVLDRNMLGEAGYWGSPEDNSLPLITMLTDIDGLESSAIGGQLMASAAT
  ESPFAQSRRIDDSTVAGVAFARYILVGCWKNLIDTLSTPLTGRMAGSSKGLAFILGAEGI
  KEQNQKERDAICMSLDGLRKAARLSCALGVAANCASALAQMAAASCVQEEKEEREAQEPS
  DAITQVKLKVEQKLEQIGKVQGVWLHTAHVLCMEAILSVGLEMGSHNPDCWPHVFRVCEY
  VGTLEHNHFSDGASQPPLTISQPQKATGSAGLLGDPECEGSPPEHSPEQGRSLSTAPVVQ
  PLSIQDLVREGSRGRASDFRGGSLMSGSSAAKVVLTLSTQADRLFEDATDKLNLMALGGF
  LYQLKKASQSQLFHSVTDTVDYSLAMPGEVKSTQDRKSALHLFRLGNAMLRIVRSKARPL
  LHVMRCWSLVAPHLVEAACHKERHVSQKAVSFIHDILTEVLTDWNEPPHFHFNEALFRPF
  ERIMQLELCDEDVQDQVVTSIGELVEVCSTQIQSGWRPLFSALETVHGGNKSEMKEYLVG
  DYSMGKGQAPVFDVFEAFLNTDNIQVFANAATSYIMCLMKFVKGLGEVDCKEIGDCAPAP
  GAPSTDLCLPALDYLRRCSQLLAKIYKMPLKPIFLSGRLAGLPRRLQEQSASSEDGIESV
  LSDFDDDTGLIEVWIILLEQLTAAVSNCPRQHQPPTLDLLFELLRDVTKTPGPGFGIYAV
  VHLLLPVMSVWLRRSHKDHSYWDMASANFKHAIGLSCELVVEHIQSFLHSDIRYESMINT
  MLKDLFELLVACVAKPTETISRVGCSCIRYVLVTAGPVFTEEMWRLACCALQDAFSATLK
  PVKDLLGCFHSGTESFSGEGCQVRVAAPSSSPSAEAEYWRIRAMAQQVFMLDTQCSPKTP
  NNFDHAQSCQLIIELPPDEKPNGHTKKSVSFREIVVSLLSHQVLLQNLYDILLEEFVKGP
  SPGEEKTIQVPEAKLAGFLRYISMQNLAVIFDLLLDSYRTAREFDTSPGLKCLLKKVSGI
  GGAANLYRQSAMSFNIYFHALVCAVLTNQETITAEQVKKVLFEDDERSTDSSQQCSSEDE
  DIFEETAQVSPPRGKEKRQWRARMPLLSVQPVSNADWVWLVKRLHKLCMELCNNYIQMHL
  DLENCMEEPPIFKGDPFFILPSFQSESSTPSTGGFSGKETPSEDDRSQSREHMGESLSLK
  AGGGDLLLPPSPKVEKKDPSRKKEWWENAGNKIYTMAADKTISKLMTEYKKRKQQHNLSA
  FPKEVKVEKKGEPLGPRGQDSPLLQRPQHLMDQGQMRHSFSAGPELLRQDKRPRSGSTGS
  SLSVSVRDAEAQIQAWTNMVLTVLNQIQILPDQTFTALQPAVFPCISQLTCHVTDIRVRQ
  AVREWLGRVGRVYDIIV
• Function: Participates in the regulation of systemic glucose homeostasis, where it negatively regulates insulin granule biogenesis in pancreatic islet beta cells. Also regulates glucagon granule production in pancreatic alpha cells. Inhibits nuclear translocation of the transcriptional coregulator PHB2 and may enhance estrogen receptor alpha (ESR1) transcriptional activity in breast cancer cells.
• Tissue Specificity: Expressed in breast cancer cell lines. Not expressed in normal tissues such as duct, mammary gland, lung, heart, liver, kidnay, bone marrow.

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Cardiovascular disease	DIS2IQDX	moderate	Biomarker	[3]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[3]
Lung cancer	DISCM4YA	moderate	Biomarker	[3]
Lung carcinoma	DISTR26C	moderate	Biomarker	[3]
Gastric cancer	DISXGOUK	Limited	Biomarker	[4]
Stomach cancer	DISKIJSX	Limited	Biomarker	[4]

12 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 Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (ARFGEF3).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (ARFGEF3).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (ARFGEF3).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (ARFGEF3).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (ARFGEF3).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (ARFGEF3).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (ARFGEF3).	[12]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (ARFGEF3).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (ARFGEF3).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (ARFGEF3).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (ARFGEF3).	[5]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (ARFGEF3).	[16]

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 Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (ARFGEF3).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (ARFGEF3).	[15]

References

• [1] Biophysical characterization of the breast cancer-related BIG3-PHB2 interaction: Effect of non-conserved loop region of BIG3 on the structure and the interaction.Biochem Biophys Res Commun. 2019 Oct 8;518(1):183-189. doi: 10.1016/j.bbrc.2019.08.028. Epub 2019 Aug 14.
• [2] Genome-wide analyses of long non-coding RNA expression profiles and functional network analysis in esophageal squamous cell carcinoma.Sci Rep. 2019 Jun 24;9(1):9162. doi: 10.1038/s41598-019-45493-5.
• [3] Screening for Early Lung Cancer, Chronic Obstructive Pulmonary Disease, and Cardiovascular Disease (the Big-3) Using Low-dose Chest Computed Tomography: Current Evidence and Technical Considerations.J Thorac Imaging. 2019 May;34(3):160-169. doi: 10.1097/RTI.0000000000000379.
• [4] CircRNA microarray profiling identifies a novel circulating biomarker for detection of gastric cancer.Mol Cancer. 2018 Sep 20;17(1):137. doi: 10.1186/s12943-018-0888-8.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 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.
• [10] 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.
• [11] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.