Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2WH1NC)

• DOT Name: Nebulette (NEBL)
• Synonyms: Actin-binding Z-disk protein
• Gene Name: NEBL
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Aural atresia, congenital
  Bladder cancer
  Cervical cancer
  Cervical carcinoma
  Dilated cardiomyopathy 1A
  Familial dilated cardiomyopathy
  HIV infectious disease
  Hypertrophic cardiomyopathy
  Multibacillary leprosy
  Non-small-cell lung cancer
  Rheumatoid arthritis
  Tuberculosis
  Urinary bladder cancer
  Urinary bladder neoplasm
  Atrial fibrillation
  Familial atrial fibrillation
  Pancreatic cancer
  Dilated cardiomyopathy
  Neoplasm
• UniProt ID: NEBL_HUMAN
• PDB ID: 4F14
• Pfam ID: PF00880 ; PF14604
• Sequence:
  MRVPVFEDIKDETEEEKIGEEENEEDQVFYKPVIEDLSMELARKCTELISDIRYKEEFKK
  SKDKCTFVTDSPMLNHVKNIGAFISEAKYKGTIKADLSNSLYKRMPATIDSVFAGEVTQL
  QSEVAYKQKHDAAKGFSDYAHMKEPPEVKHAMEVNKHQSNISYRKDVQDTHTYSAELDRP
  DIKMATQISKIISNAEYKKGQGIMNKEPAVIGRPDFEHAVEASKLSSQIKYKEKFDNEMK
  DKKHHYNPLESASFRQNQLAATLASNVKYKKDIQNMHDPVSDLPNLLFLDHVLKASKMLS
  GREYKKLFEENKGMYHFDADAVEHLHHKGNAVLQSQVKYKEEYEKNKGKPMLEFVETPSY
  QASKEAQKMQSEKVYKEDFEKEIKGRSSLDLDKTPEFLHVKYITNLLREKEYKKDLENEI
  KGKGMELNSEVLDIQRAKRASEMASEKEYKKDLESIIKGKGMQAGTDTLEMQHAKKAAEI
  ASEKDYKRDLETEIKGKGMQVSTDTLDVQRAKKASEMASQKQYKKDLENEIKGKGMQVSM
  DIPDILRAKRTSEIYSQRKYKDEAEKMLSNYSTIADTPEIQRIKTTQQNISAVFYKKEVG
  AGTAVKDSPEIERVKKNQQNISSVKYKEEIKHATAISDPPELKRVKENQKNISNLQYKEQ
  NYKATPVSMTPEIERVRRNQEQLSAVKYKGELQRGTAISDPPELKRAKENQKNISNVYYR
  GQLGRATTLSVTPEMERVKKNQENISSVKYTQDHKQMKGRPSLILDTPAMRHVKEAQNHI
  SMVKYHEDFEKTKGRGFTPVVDDPVTERVRKNTQVVSDAAYKGVHPHIVEMDRRPGIIVD
  LKVWRTDPGSIFDLDPLEDNIQSRSLHMLSEKASHYRRHWSRSHSSSTFGTGLGDDRSEI
  SEIYPSFSCCSEVTRPSDEGAPVLPGAYQQSHSQGYGYMHQTSVSSMRSMQHSPNLRTYR
  AMYDYSAQDEDEVSFRDGDYIVNVQPIDDGWMYGTVQRTGRTGMLPANYIEFVN
• Function: Binds to actin and plays an important role in the assembly of the Z-disk. May functionally link sarcomeric actin to the desmin intermediate filaments in the heart muscle sarcomeres. Isoform 2 might play a role in the assembly of focal adhesion.
• Tissue Specificity: Abundantly expressed in cardiac muscle, but not in skeletal or smooth muscle. Localized to Z-lines in cardiac cells and to dense bodies in nonmuscle cells. Isoform 2 is expressed in non-muscle cells such as in fibroblasts.
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Aural atresia, congenital	DISCP7UV	Strong	Genetic Variation	[3]
Bladder cancer	DISUHNM0	Strong	Biomarker	[2]
Cervical cancer	DISFSHPF	Strong	Biomarker	[4]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[4]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[5]
Familial dilated cardiomyopathy	DISBHDU9	Strong	Genetic Variation	[6]
HIV infectious disease	DISO97HC	Strong	Genetic Variation	[7]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Biomarker	[8]
Multibacillary leprosy	DIS90T7X	Strong	Genetic Variation	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[11]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[7]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[2]
Atrial fibrillation	DIS15W6U	moderate	Genetic Variation	[12]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[12]
Pancreatic cancer	DISJC981	moderate	Altered Expression	[13]
Dilated cardiomyopathy	DISX608J	Limited	Autosomal dominant	[14]
Neoplasm	DISZKGEW	Limited	Altered Expression	[13]

17 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 Nebulette (NEBL).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Nebulette (NEBL).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Nebulette (NEBL).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Nebulette (NEBL).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nebulette (NEBL).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Nebulette (NEBL).	[20]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Nebulette (NEBL).	[15]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Nebulette (NEBL).	[22]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Nebulette (NEBL).	[23]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Nebulette (NEBL).	[24]
Melphalan	DMOLNHF	Approved	Melphalan increases the expression of Nebulette (NEBL).	[25]
Bicalutamide	DMZMSPF	Approved	Bicalutamide increases the expression of Nebulette (NEBL).	[26]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Nebulette (NEBL).	[27]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Nebulette (NEBL).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Nebulette (NEBL).	[30]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Nebulette (NEBL).	[31]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Nebulette (NEBL).	[32]

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 Nebulette (NEBL).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Nebulette (NEBL).	[29]

References

• [1] Nebulette is the second member of the nebulin family fused to the MLL gene in infant leukemia.Cancer Genet Cytogenet. 2010 Apr 15;198(2):151-4. doi: 10.1016/j.cancergencyto.2009.12.013.
• [2] LASP2 suppressed malignancy and Wnt/-catenin signaling pathway activation in bladder cancer.Exp Ther Med. 2018 Dec;16(6):5215-5223. doi: 10.3892/etm.2018.6836. Epub 2018 Oct 9.
• [3] Genome-Wide Association Study Identifies Novel Susceptibility Genes Associated with Coronary Artery Aneurysm Formation in Kawasaki Disease.PLoS One. 2016 May 12;11(5):e0154943. doi: 10.1371/journal.pone.0154943. eCollection 2016.
• [4] Knockdown of LASP2 inhibits the proliferation, migration, and invasion of cervical cancer cells.J Cell Biochem. 2019 Sep;120(9):15389-15396. doi: 10.1002/jcb.28806. Epub 2019 Apr 26.
• [5] Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis.J Am Coll Cardiol. 2010 Oct 26;56(18):1493-502. doi: 10.1016/j.jacc.2010.05.045.
• [6] Mutations in NEBL encoding the cardiac Z-disk protein nebulette are associated with various cardiomyopathies.Arch Med Sci. 2016 Apr 1;12(2):263-78. doi: 10.5114/aoms.2016.59250. Epub 2016 Apr 11.
• [7] Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs.OMICS. 2017 Apr;21(4):207-216. doi: 10.1089/omi.2017.0019.
• [8] Genetics of sudden cardiac death syndromes.Curr Opin Cardiol. 2011 May;26(3):196-203. doi: 10.1097/HCO.0b013e3283459893.
• [9] CUBN and NEBL common variants in the chromosome 10p13 linkage region are associated with multibacillary leprosy in Vietnam.Hum Genet. 2014 Jul;133(7):883-93. doi: 10.1007/s00439-014-1430-8. Epub 2014 Feb 23.
• [10] Lasp2 enhances tumor invasion via facilitating phosphorylation of FAK and predicts poor overall survival of non-small cell lung cancer patients.Mol Carcinog. 2017 Dec;56(12):2558-2565. doi: 10.1002/mc.22700. Epub 2017 Aug 3.
• [11] Genome-wide association study of response to tumour necrosis factor inhibitor therapy in rheumatoid arthritis.Pharmacogenomics J. 2018 Sep;18(5):657-664. doi: 10.1038/s41397-018-0040-6. Epub 2018 Aug 31.
• [12] Identification of six new genetic loci associated with atrial fibrillation in the Japanese population.Nat Genet. 2017 Jun;49(6):953-958. doi: 10.1038/ng.3842. Epub 2017 Apr 17.
• [13] Upregulation of LASP2 inhibits pancreatic cancer cell migration and invasion through suppressing TGF--induced EMT.J Cell Biochem. 2019 Aug;120(8):13651-13657. doi: 10.1002/jcb.28638. Epub 2019 Apr 4.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
• [18] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [19] 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.
• [20] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [21] 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.
• [22] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [23] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [24] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [25] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [26] Microarray analysis of bicalutamide action on telomerase activity, p53 pathway and viability of prostate carcinoma cell lines. J Pharm Pharmacol. 2005 Jan;57(1):83-92.
• [27] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [32] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.