Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYLY5TY)

• DOT Name: Neurobeachin (NBEA)
• Synonyms: Lysosomal-trafficking regulator 2; Protein BCL8B
• Gene Name: NBEA
• Related Disease:
  Complex neurodevelopmental disorder
  Autism
  Autism spectrum disorder
  Bladder cancer
  Fragile X syndrome
  Intellectual disability
  Neoplasm
  Neurodevelopmental disorder with or without early-onset generalized epilepsy
  Syndromic intellectual disability
  Plasma cell myeloma
• UniProt ID: NBEA_HUMAN
• PDB ID: 1MI1
• Pfam ID: PF02138 ; PF06469 ; PF15787 ; PF13385 ; PF20426 ; PF20425 ; PF14844
• Sequence:
  MASEKPGPGPGLEPQPVGLIAVGAAGGGGGGSGGGGTGGSGMGELRGASGSGSVMLPAGM
  INPSVPIRNIRMKFAVLIGLIQVGEVSNRDIVETVLNLLVGGEFDLEMNFIIQDAESITC
  MTELLEHCDVTCQAEIWSMFTAILRKSVRNLQTSTEVGLIEQVLLKMSAVDDMIADLLVD
  MLGVLASYSITVKELKLLFSMLRGESGIWPRHAVKLLSVLNQMPQRHGPDTFFNFPGCSA
  AAIALPPIAKWPYQNGFTLNTWFRMDPLNNINVDKDKPYLYCFRTSKGVGYSAHFVGNCL
  IVTSLKSKGKGFQHCVKYDFQPRKWYMISIVHIYNRWRNSEIRCYVNGQLVSYGDMAWHV
  NTNDSYDKCFLGSSETADANRVFCGQLGAVYVFSEALNPAQIFAIHQLGPGYKSTFKFKS
  ESDIHLAEHHKQVLYDGKLASSIAFTYNAKATDAQLCLESSPKENASIFVHSPHALMLQD
  VKAIVTHSIHSAIHSIGGIQVLFPLFAQLDNRQLNDSQVETTVCATLLAFLVELLKSSVA
  MQEQMLGGKGFLVIGYLLEKSSRVHITRAVLEQFLSFAKYLDGLSHGAPLLKQLCDHILF
  NPAIWIHTPAKVQLSLYTYLSAEFIGTATIYTTIRRVGTVLQLMHTLKYYYWVINPADSS
  GITPKGLDGPRPSQKEIISLRAFMLLFLKQLILKDRGVKEDELQSILNYLLTMHEDENIH
  DVLQLLVALMSEHPASMIPAFDQRNGIRVIYKLLASKSESIWVQALKVLGYFLKHLGHKR
  KVEIMHTHSLFTLLGERLMLHTNTVTVTTYNTLYEILTEQVCTQVVHKPHPEPDSTVKIQ
  NPMILKVVATLLKNSTPSAELMEVRRLFLSDMIKLFSNSRENRRCLLQCSVWQDWMFSLG
  YINPKNSEEQKITEMVYNIFRILLYHAIKYEWGGWRVWVDTLSIAHSKVTYEAHKEYLAK
  MYEEYQRQEEENIKKGKKGNVSTISGLSSQTTGAKGGMEIREIEDLSQSQSPESETDYPV
  STDTRDLLMSTKVSDDILGNSDRPGSGVHVEVHDLLVDIKAEKVEATEVKLDDMDLSPET
  LVGGENGALVEVESLLDNVYSAAVEKLQNNVHGSVGIIKKNEEKDNGPLITLADEKEDLP
  NSSTSFLFDKIPKQEEKLLPELSSNHIIPNIQDTQVHLGVSDDLGLLAHMTGSVDLTCTS
  SIIEEKEFKIHTTSDGMSSISERDLASSTKGLEYAEMTATTLETESSSSKIVPNIDAGSI
  ISDTERSDDGKESGKEIRKIQTTTTTQAVQGRSITQQDRDLRVDLGFRGMPMTEEQRRQF
  SPGPRTTMFRIPEFKWSPMHQRLLTDLLFALETDVHVWRSHSTKSVMDFVNSNENIIFVH
  NTIHLISQMVDNIIIACGGILPLLSAATSPTGSKTELENIEVTQGMSAETAVTFLSRLMA
  MVDVLVFASSLNFSEIEAEKNMSSGGLMRQCLRLVCCVAVRNCLECRQRQRDRGNKSSHG
  SSKPQEVPQSVTATAASKTPLENVPGNLSPIKDPDRLLQDVDINRLRAVVFRDVDDSKQA
  QFLALAVVYFISVLMVSKYRDILEPQRETTRTGSQPGRNIRQEINSPTSTVVVIPSIPHP
  SLNHGFLAKLIPEQSFGHSFYKETPAAFPDTIKEKETPTPGEDIQVESSIPHTDSGIGEE
  QVASILNGAELETSTGPDAMSELLSTLSSEVKKSQESLTENPSETLKPATSISSISQTKG
  INVKEILKSLVAAPVEIAECGPEPIPYPDPALKRETQAILPMQFHSFDRSVVVPVKKPPP
  GSLAVTTVGATTAGSGLPTGSTSNIFAATGATPKSMINTTGAVDSGSSSSSSSSSFVNGA
  TSKNLPAVQTVAPMPEDSAENMSITAKLERALEKVAPLLREIFVDFAPFLSRTLLGSHGQ
  ELLIEGLVCMKSSTSVVELVMLLCSQEWQNSIQKNAGLAFIELINEGRLLCHAMKDHIVR
  VANEAEFILNRQRAEDVHKHAEFESQCAQYAADRREEEKMCDHLISAAKHRDHVTANQLK
  QKILNILTNKHGAWGAVSHSQLHDFWRLDYWEDDLRRRRRFVRNAFGSTHAEALLKAAIE
  YGTEEDVVKSKKTFRSQAIVNQNAETELMLEGDDDAVSLLQEKEIDNLAGPVVLSTPAQL
  IAPVVVAKGTLSITTTEIYFEVDEDDSAFKKIDTKVLAYTEGLHGKWMFSEIRAVFSRRY
  LLQNTALEVFMANRTSVMFNFPDQATVKKVVYSLPRVGVGTSYGLPQARRISLATPRQLY
  KSSNMTQRWQRREISNFEYLMFLNTIAGRTYNDLNQYPVFPWVLTNYESEELDLTLPGNF
  RDLSKPIGALNPKRAVFYAERYETWEDDQSPPYHYNTHYSTATSTLSWLVRIEPFTTFFL
  NANDGKFDHPDRTFSSVARSWRTSQRDTSDVKELIPEFYYLPEMFVNSNGYNLGVREDEV
  VVNDVDLPPWAKKPEDFVRINRMALESEFVSCQLHQWIDLIFGYKQRGPEAVRALNVFHY
  LTYEGSVNLDSITDPVLREAMEAQIQNFGQTPSQLLIEPHPPRSSAMHLCFLPQSPLMFK
  DQMQQDVIMVLKFPSNSPVTHVAANTLPHLTIPAVVTVTCSRLFAVNRWHNTVGLRGAPG
  YSLDQAHHLPIEMDPLIANNSGVNKRQITDLVDQSIQINAHCFVVTADNRYILICGFWDK
  SFRVYSTETGKLTQIVFGHWDVVTCLARSESYIGGDCYIVSGSRDATLLLWYWSGRHHII
  GDNPNSSDYPAPRAVLTGHDHEVVCVSVCAELGLVISGAKEGPCLVHTITGDLLRALEGP
  ENCLFPRLISVSSEGHCIIYYERGRFSNFSINGKLLAQMEINDSTRAILLSSDGQNLVTG
  GDNGVVEVWQACDFKQLYIYPGCDAGIRAMDLSHDQRTLITGMASGSIVAFNIDFNRWHY
  EHQNRY
• Function: Binds to type II regulatory subunits of protein kinase A and anchors/targets them to the membrane. May anchor the kinase to cytoskeletal and/or organelle-associated proteins.
• Tissue Specificity: Predominant in many brain structures. Also expressed at medium levels in spleen, thymus, prostate, testis and ovary. Low level expression is seen in heart, kidney, pancreas, skeletal muscle and intestine.
• Reactome Pathway:
  PKA activation (R-HSA-163615)
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)
  Assembly and cell surface presentation of NMDA receptors (R-HSA-9609736)
  Neurotransmitter receptors and postsynaptic signal transmission (R-HSA-112314)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[1]
Autism	DISV4V1Z	Strong	Biomarker	[2]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[3]
Bladder cancer	DISUHNM0	Strong	Genetic Variation	[4]
Fragile X syndrome	DISE8W3A	Strong	Biomarker	[3]
Intellectual disability	DISMBNXP	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Neurodevelopmental disorder with or without early-onset generalized epilepsy	DISUW80D	Strong	Autosomal dominant	[7]
Syndromic intellectual disability	DISH7SDF	Strong	Autosomal dominant	[2]
Plasma cell myeloma	DIS0DFZ0	Limited	Biomarker	[8]

14 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 Neurobeachin (NBEA).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Neurobeachin (NBEA).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Neurobeachin (NBEA).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Neurobeachin (NBEA).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Neurobeachin (NBEA).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Neurobeachin (NBEA).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Neurobeachin (NBEA).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Neurobeachin (NBEA).	[16]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Neurobeachin (NBEA).	[17]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Neurobeachin (NBEA).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Neurobeachin (NBEA).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Neurobeachin (NBEA).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Neurobeachin (NBEA).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Neurobeachin (NBEA).	[22]

References

• [1] 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.
• [2] NBEA: Developmental disease gene with early generalized epilepsy phenotypes. Ann Neurol. 2018 Nov;84(5):788-795. doi: 10.1002/ana.25350. Epub 2018 Oct 25.
• [3] Fragile X Mental Retardation Protein positively regulates PKA anchor Rugose and PKA activity to control actin assembly in learning/memory circuitry.Neurobiol Dis. 2019 Jul;127:53-64. doi: 10.1016/j.nbd.2019.02.004. Epub 2019 Feb 13.
• [4] Genome-wide Association Study for Tumour Stage, Grade, Size, and Age at Diagnosis of Non-muscle-invasive Bladder Cancer.Eur Urol Oncol. 2019 Jul;2(4):381-389. doi: 10.1016/j.euo.2018.08.020. Epub 2018 Sep 15.
• [5] Haploinsufficiency of the autism candidate gene Neurobeachin induces autism-like behaviors and affects cellular and molecular processes of synaptic plasticity in mice.Neurobiol Dis. 2013 Mar;51:144-51. doi: 10.1016/j.nbd.2012.11.004. Epub 2012 Nov 12.
• [6] Neurobeachin (NBEA) is a target of recurrent interstitial deletions at 13q13 in patients with MGUS and multiple myeloma.Exp Hematol. 2009 Feb;37(2):234-44. doi: 10.1016/j.exphem.2008.10.014.
• [7] Genomic diagnosis for children with intellectual disability and/or developmental delay. Genome Med. 2017 May 30;9(1):43. doi: 10.1186/s13073-017-0433-1.
• [8] Frequent PVT1 rearrangement and novel chimeric genes PVT1-NBEA and PVT1-WWOX occur in multiple myeloma with 8q24 abnormality.Cancer Res. 2012 Oct 1;72(19):4954-62. doi: 10.1158/0008-5472.CAN-12-0213. Epub 2012 Aug 6.
• [9] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [15] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [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] 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.
• [18] A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer. Toxicol Appl Pharmacol. 2015 Jun 1;285(2):79-88.
• [19] 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.
• [20] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [21] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [22] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.