Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1EWGRW)

• DOT Name: Adhesion G protein-coupled receptor B3 (ADGRB3)
• Synonyms: Brain-specific angiogenesis inhibitor 3
• Gene Name: ADGRB3
• Related Disease:
  Primary sclerosing cholangitis
  Adult glioblastoma
  Autism
  Brain neoplasm
  Cerebellar ataxia
  Glioblastoma multiforme
  Intellectual disability
  Malignant glioma
  Mental disorder
  Neoplasm
  Small-cell lung cancer
  Acute myelogenous leukaemia
  Venous thromboembolism
• UniProt ID: AGRB3_HUMAN
• PDB ID: 4DLO
• Pfam ID: PF00002 ; PF19188 ; PF16489 ; PF01825 ; PF02793 ; PF00090
• Sequence:
  MKAVRNLLIYIFSTYLLVMFGFNAAQDFWCSTLVKGVIYGSYSVSEMFPKNFTNCTWTLE
  NPDPTKYSIYLKFSKKDLSCSNFSLLAYQFDHFSHEKIKDLLRKNHSIMQLCNSKNAFVF
  LQYDKNFIQIRRVFPTNFPGLQKKGEEDQKSFFEFLVLNKVSPSQFGCHVLCTWLESCLK
  SENGRTESCGIMYTKCTCPQHLGEWGIDDQSLILLNNVVLPLNEQTEGCLTQELQTTQVC
  NLTREAKRPPKEEFGMMGDHTIKSQRPRSVHEKRVPQEQADAAKFMAQTGESGVEEWSQW
  STCSVTCGQGSQVRTRTCVSPYGTHCSGPLRESRVCNNTALCPVHGVWEEWSPWSLCSFT
  CGRGQRTRTRSCTPPQYGGRPCEGPETHHKPCNIALCPVDGQWQEWSSWSQCSVTCSNGT
  QQRSRQCTAAAHGGSECRGPWAESRECYNPECTANGQWNQWGHWSGCSKSCDGGWERRIR
  TCQGAVITGQQCEGTGEEVRRCNEQRCPAPYEICPEDYLMSMVWKRTPAGDLAFNQCPLN
  ATGTTSRRCSLSLHGVAFWEQPSFARCISNEYRHLQHSIKEHLAKGQRMLAGDGMSQVTK
  TLLDLTQRKNFYAGDLLMSVEILRNVTDTFKRASYIPASDGVQNFFQIVSNLLDEENKEK
  WEDAQQIYPGSIELMQVIEDFIHIVGMGMMDFQNSYLMTGNVVASIQKLPAASVLTDINF
  PMKGRKGMVDWARNSEDRVVIPKSIFTPVSSKELDESSVFVLGAVLYKNLDLILPTLRNY
  TVINSKIIVVTIRPEPKTTDSFLEIELAHLANGTLNPYCVLWDDSKTNESLGTWSTQGCK
  TVLTDASHTKCLCDRLSTFAILAQQPREIIMESSGTPSVTLIVGSGLSCLALITLAVVYA
  ALWRYIRSERSIILINFCLSIISSNILILVGQTQTHNKSICTTTTAFLHFFFLASFCWVL
  TEAWQSYMAVTGKIRTRLIRKRFLCLGWGLPALVVATSVGFTRTKGYGTDHYCWLSLEGG
  LLYAFVGPAAAVVLVNMVIGILVFNKLVSRDGILDKKLKHRAGQMSEPHSGLTLKCAKCG
  VVSTTALSATTASNAMASLWSSCVVLPLLALTWMSAVLAMTDKRSILFQILFAVFDSLQG
  FVIVMVHCILRREVQDAFRCRLRNCQDPINADSSSSFPNGHAQIMTDFEKDVDIACRSVL
  HKDIGPCRAATITGTLSRISLNDDEEEKGTNPEGLSYSTLPGNVISKVIIQQPTGLHMPM
  SMNELSNPCLKKENSELRRTVYLCTDDNLRGADMDIVHPQERMMESDYIVMPRSSVNNQP
  SMKEESKMNIGMETLPHERLLHYKVNPEFNMNPPVMDQFNMNLEQHLAPQEHMQNLPFEP
  RTAVKNFMASELDDNAGLSRSETGSTISMSSLERRKSRYSDLDFEKVMHTRKRHMELFQE
  LNQKFQTLDRFRDIPNTSSMENPAPNKNPWDTFKNPSEYPHYTTINVLDTEAKDALELRP
  AEWEKCLNLPLDVQEGDFQTEV
• Function: Receptor that plays a role in the regulation of synaptogenesis and dendritic spine formation at least partly via interaction with ELMO1 and RAC1 activity. Promotes myoblast fusion through ELMO/DOCK1.
• Tissue Specificity: Strongly expressed in brain. Also detected in heart. Reduced expression in some glioblastoma cell lines.

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Primary sclerosing cholangitis	DISTH5WJ	Definitive	Genetic Variation	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[2]
Autism	DISV4V1Z	Strong	Biomarker	[3]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[4]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[5]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[5]
Malignant glioma	DISFXKOV	Strong	Altered Expression	[4]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	moderate	Biomarker	[6]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[6]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[7]
Venous thromboembolism	DISUR7CR	Limited	Genetic Variation	[8]

6 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 Adhesion G protein-coupled receptor B3 (ADGRB3).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Adhesion G protein-coupled receptor B3 (ADGRB3).	[11]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Adhesion G protein-coupled receptor B3 (ADGRB3).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Adhesion G protein-coupled receptor B3 (ADGRB3).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Adhesion G protein-coupled receptor B3 (ADGRB3).	[16]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Adhesion G protein-coupled receptor B3 (ADGRB3).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Adhesion G protein-coupled receptor B3 (ADGRB3).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Adhesion G protein-coupled receptor B3 (ADGRB3).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Adhesion G protein-coupled receptor B3 (ADGRB3).	[15]

References

• [1] A novel approach to genome-wide association analysis identifies genetic associations with primary biliary cholangitis and primary sclerosing cholangitis in Polish patients.BMC Med Genomics. 2017 Jan 6;10(1):2. doi: 10.1186/s12920-016-0239-9.
• [2] Cloning and characterization of BAI2 and BAI3, novel genes homologous to brain-specific angiogenesis inhibitor 1 (BAI1).Cytogenet Cell Genet. 1997;79(1-2):103-8. doi: 10.1159/000134693.
• [3] The phenotypic spectrum of proximal 6q deletions based on a large cohort derived from social media and literature reports.Eur J Hum Genet. 2018 Oct;26(10):1478-1489. doi: 10.1038/s41431-018-0172-9. Epub 2018 Jun 8.
• [4] Expression of brain-specific angiogenesis inhibitor 3 (BAI3) in normal brain and implications for BAI3 in ischemia-induced brain angiogenesis and malignant glioma.FEBS Lett. 2004 Jul 2;569(1-3):307-16. doi: 10.1016/j.febslet.2004.06.011.
• [5] Biallelic intragenic duplication in ADGRB3 (BAI3) gene associated with intellectual disability, cerebellar atrophy, and behavioral disorder.Eur J Hum Genet. 2019 Apr;27(4):594-602. doi: 10.1038/s41431-018-0321-1. Epub 2019 Jan 18.
• [6] BAI3, CDX2 and VIL1: a panel of three antibodies to distinguish small cell from large cell neuroendocrine lung carcinomas.Histopathology. 2014 Mar;64(4):547-56. doi: 10.1111/his.12278. Epub 2013 Nov 25.
• [7] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [8] A multi-stage multi-design strategy provides strong evidence that the BAI3 locus is associated with early-onset venous thromboembolism.J Thromb Haemost. 2010 Dec;8(12):2671-9. doi: 10.1111/j.1538-7836.2010.04092.x.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [11] 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.
• [12] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [13] 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.
• [14] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [15] 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.
• [16] 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.
• [17] Early gene response in lithium chloride induced apoptosis. Apoptosis. 2005 Jan;10(1):75-90. doi: 10.1007/s10495-005-6063-x.