Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKB0B0H)

• DOT Name: Nexilin (NEXN)
• Synonyms: F-actin-binding protein; Nelin
• Gene Name: NEXN
• Related Disease:
  Familial dilated cardiomyopathy
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Vascular disease
  Cardiomyopathy
  Dilated cardiomyopathy
  Obsolete familial isolated dilated cardiomyopathy
  Atrial septal defect
  Coronary atherosclerosis
  Coronary heart disease
  Dilated cardiomyopathy 1CC
  Hyperglycemia
  Hypertrophic cardiomyopathy
  Hypertrophic cardiomyopathy 20
  Neoplasm
  Subarachnoid hemorrhage
• UniProt ID: NEXN_HUMAN
• Pfam ID: PF07679
• Sequence:
  MNDISQKAEILLSSSKPVPKTYVPKLGKGDVKDKFEAMQRAREERNQRRSRDEKQRRKEQ
  YIREREWNRRKQEIKEMLASDDEEDVSSKVEKAYVPKLTGTVKGRFAEMEKQRQEEQRKR
  TEEERKRRIEQDMLEKRKIQRELAKRAEQIEDINNTGTESASEEGDDSLLITVVPVKSYK
  TSGKMKKNFEDLEKEREEKERIKYEEDKRIRYEEQRPSLKEAKCLSLVMDDEIESEAKKE
  SLSPGKLKLTFEELERQRQENRKKQAEEEARKRLEEEKRAFEEARRQMVNEDEENQDTAK
  IFKGYRPGKLKLSFEEMERQRREDEKRKAEEEARRRIEEEKKAFAEARRNMVVDDDSPEM
  YKTISQEFLTPGKLEINFEELLKQKMEEEKRRTEEERKHKLEMEKQEFEQLRQEMGEEEE
  ENETFGLSREYEELIKLKRSGSIQAKNLKSKFEKIGQLSEKEIQKKIEEERARRRAIDLE
  IKEREAENFHEEDDVDVRPARKSEAPFTHKVNMKARFEQMAKAREEEEQRRIEEQKLLRM
  QFEQREIDAALQKKREEEEEEEGSIMNGSTAEDEEQTRSGAPWFKKPLKNTSVVDSEPVR
  FTVKVTGEPKPEITWWFEGEILQDGEDYQYIERGETYCLYLPETFPEDGGEYMCKAVNNK
  GSAASTCILTIESKN
• Function: Involved in regulating cell migration through association with the actin cytoskeleton. Has an essential role in the maintenance of Z line and sarcomere integrity.
• Tissue Specificity: Abundantly expressed in heart and skeletal muscle, and at lower levels in placenta, lung, liver and pancreas. Also expressed in HeLaS3 and MOLT-4 cell lines.

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial dilated cardiomyopathy	DISBHDU9	Definitive	GermlineCausalMutation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[3]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[3]
Vascular disease	DISVS67S	Strong	Biomarker	[4]
Cardiomyopathy	DISUPZRG	moderate	Biomarker	[5]
Dilated cardiomyopathy	DISX608J	Moderate	Autosomal dominant	[6]
Obsolete familial isolated dilated cardiomyopathy	DIS4FXO4	Supportive	Autosomal dominant	[1]
Atrial septal defect	DISJT76B	Limited	Genetic Variation	[7]
Coronary atherosclerosis	DISKNDYU	Limited	Altered Expression	[8]
Coronary heart disease	DIS5OIP1	Limited	Altered Expression	[8]
Dilated cardiomyopathy 1CC	DISQ019P	Limited	Autosomal dominant	[1]
Hyperglycemia	DIS0BZB5	Limited	Biomarker	[9]
Hypertrophic cardiomyopathy	DISQG2AI	Limited	Autosomal dominant	[6]
Hypertrophic cardiomyopathy 20	DISCTEAT	Limited	Autosomal dominant	[10]
Neoplasm	DISZKGEW	Limited	Biomarker	[11]
Subarachnoid hemorrhage	DISI7I8Y	Limited	Biomarker	[12]

19 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 Nexilin (NEXN).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Nexilin (NEXN).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Nexilin (NEXN).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nexilin (NEXN).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Nexilin (NEXN).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Nexilin (NEXN).	[18]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Nexilin (NEXN).	[19]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Nexilin (NEXN).	[20]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Nexilin (NEXN).	[21]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Nexilin (NEXN).	[22]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Nexilin (NEXN).	[23]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Nexilin (NEXN).	[24]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Nexilin (NEXN).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Nexilin (NEXN).	[27]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Nexilin (NEXN).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Nexilin (NEXN).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Nexilin (NEXN).	[29]
Resorcinol	DMM37C0	Investigative	Resorcinol decreases the expression of Nexilin (NEXN).	[32]
1,6-hexamethylene diisocyanate	DMLB3RT	Investigative	1,6-hexamethylene diisocyanate affects the expression of Nexilin (NEXN).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Nexilin (NEXN).	[26]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Nexilin (NEXN).	[30]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Nexilin (NEXN).	[31]

References

• [1] Nexilin mutations destabilize cardiac Z-disks and lead to dilated cardiomyopathy. Nat Med. 2009 Nov;15(11):1281-8. doi: 10.1038/nm.2037. Epub 2009 Nov 1.
• [2] Coactosin-like protein CLP/Cotl1 suppresses breast cancer growth through activation of IL-24/PERP and inhibition of non-canonical TGF signaling.Oncogene. 2018 Jan 18;37(3):323-331. doi: 10.1038/onc.2017.342. Epub 2017 Sep 18.
• [3] Atorvastatin inhibits pyroptosis through the lncRNA NEXN-AS1/NEXN pathway in human vascular endothelial cells.Atherosclerosis. 2020 Jan;293:26-34. doi: 10.1016/j.atherosclerosis.2019.11.033. Epub 2019 Dec 3.
• [4] NEXN is a novel susceptibility gene for coronary artery disease in Han Chinese.PLoS One. 2013 Dec 11;8(12):e82135. doi: 10.1371/journal.pone.0082135. eCollection 2013.
• [5] Nexilin Is a New Component of Junctional Membrane Complexes Required for Cardiac T-Tubule Formation.Circulation. 2019 Jul 2;140(1):55-66. doi: 10.1161/CIRCULATIONAHA.119.039751. Epub 2019 Apr 15.
• [6] 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.
• [7] NEXN inhibits GATA4 and leads to atrial septal defects in mice and humans.Cardiovasc Res. 2014 Jul 15;103(2):228-37. doi: 10.1093/cvr/cvu134. Epub 2014 May 27.
• [8] Long noncoding RNA NEXN-AS1 mitigates atherosclerosis by regulating the actin-binding protein NEXN.J Clin Invest. 2019 Mar 1;129(3):1115-1128. doi: 10.1172/JCI98230. Epub 2019 Feb 4.
• [9] Transcription Factor CREM Mediates High Glucose Response in Cardiomyocytes and in a Male Mouse Model of Prolonged Hyperglycemia.Endocrinology. 2017 Jul 1;158(7):2391-2405. doi: 10.1210/en.2016-1960.
• [10] Mutations in NEXN, a Z-disc gene, are associated with hypertrophic cardiomyopathy. Am J Hum Genet. 2010 Nov 12;87(5):687-93. doi: 10.1016/j.ajhg.2010.10.002. Epub 2010 Oct 21.
• [11] Cortactin overexpression regulates actin-related protein 2/3 complex activity, motility, and invasion in carcinomas with chromosome 11q13 amplification.Cancer Res. 2006 Aug 15;66(16):8017-25. doi: 10.1158/0008-5472.CAN-05-4490.
• [12] Nexilin Regulates Oligodendrocyte Progenitor Cell Migration and Remyelination and Is Negatively Regulated by Protease-Activated Receptor 1/Ras-Proximate-1 Signaling Following Subarachnoid Hemorrhage.Front Neurol. 2018 Apr 25;9:282. doi: 10.3389/fneur.2018.00282. eCollection 2018.
• [13] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [14] 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.
• [15] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [16] 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.
• [17] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [18] 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.
• [19] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [20] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [21] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [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] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [25] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [26] 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.
• [27] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [28] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [29] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [30] 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.
• [31] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.
• [32] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [33] Gene profiles of THP-1 macrophages after in vitro exposure to respiratory (non-)sensitizing chemicals: identification of discriminating genetic markers and pathway analysis. Toxicol In Vitro. 2009 Sep;23(6):1151-62. doi: 10.1016/j.tiv.2009.06.007. Epub 2009 Jun 13.