Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAGFML5)

• DOT Name: Nuclear distribution protein nudE-like 1 (NDEL1)
• Synonyms: Protein Nudel; Mitosin-associated protein 1
• Gene Name: NDEL1
• Related Disease:
  Autism
  Behcet disease
  Bipolar disorder
  Depression
  Disorder of orbital region
  Glioma
  Iritis
  Lissencephaly spectrum disorders
  Nervous system disease
  Status epilepticus seizure
  Isolated congenital microcephaly
  Mental disorder
  Neurodevelopmental disorder
  Arthritis
  Juvenile idiopathic arthritis
• UniProt ID: NDEL1_HUMAN
• PDB ID: 2V66
• Pfam ID: PF04880
• Sequence:
  MDGEDIPDFSSLKEETAYWKELSLKYKQSFQEARDELVEFQEGSRELEAELEAQLVQAEQ
  RNRDLQADNQRLKYEVEALKEKLEHQYAQSYKQVSVLEDDLSQTRAIKEQLHKYVRELEQ
  ANDDLERAKRATIVSLEDFEQRLNQAIERNAFLESELDEKESLLVSVQRLKDEARDLRQE
  LAVRERQQEVTRKSAPSSPTLDCEKMDSAVQASLSLPATPVGKGTENTFPSPKAIPNGFG
  TSPLTPSARISALNIVGDLLRKVGALESKLAACRNFAKDQASRKSYISGNVNCGVLNGNG
  TKFSRSGHTSFFDKGAVNGFDPAPPPPGLGSSRPSSAPGMLPLSV
• Function: Required for organization of the cellular microtubule array and microtubule anchoring at the centrosome. May regulate microtubule organization at least in part by targeting the microtubule severing protein KATNA1 to the centrosome. Also positively regulates the activity of the minus-end directed microtubule motor protein dynein. May enhance dynein-mediated microtubule sliding by targeting dynein to the microtubule plus ends. Required for several dynein- and microtubule-dependent processes such as the maintenance of Golgi integrity, the centripetal motion of secretory vesicles and the coupling of the nucleus and centrosome. Also required during brain development for the migration of newly formed neurons from the ventricular/subventricular zone toward the cortical plate. Plays a role, together with DISC1, in the regulation of neurite outgrowth. Required for mitosis in some cell types but appears to be dispensible for mitosis in cortical neuronal progenitors, which instead requires NDE1. Facilitates the polymerization of neurofilaments from the individual subunits NEFH and NEFL. Positively regulates lysosome peripheral distribution and ruffled border formation in osteoclasts.
• Tissue Specificity: Expressed in brain, heart, kidney, liver, lung, pancreas, placenta and skeletal muscle.
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  RHO GTPases Activate Formins (R-HSA-5663220)
  Mitotic Prometaphase (R-HSA-68877)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Strong	Genetic Variation	[1]
Behcet disease	DISSYMBS	Strong	Altered Expression	[2]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[3]
Depression	DIS3XJ69	Strong	Altered Expression	[4]
Disorder of orbital region	DISH0ECJ	Strong	Biomarker	[5]
Glioma	DIS5RPEH	Strong	Biomarker	[6]
Iritis	DISSA7AC	Strong	Genetic Variation	[5]
Lissencephaly spectrum disorders	DISBCZL7	Strong	Biomarker	[7]
Nervous system disease	DISJ7GGT	Strong	Biomarker	[7]
Status epilepticus seizure	DISY3BIC	Strong	Altered Expression	[8]
Isolated congenital microcephaly	DISUXHZ6	moderate	Biomarker	[9]
Mental disorder	DIS3J5R8	moderate	Biomarker	[9]
Neurodevelopmental disorder	DIS372XH	moderate	Biomarker	[9]
Arthritis	DIST1YEL	Limited	Biomarker	[10]
Juvenile idiopathic arthritis	DISQZGBV	Limited	Biomarker	[11]

7 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Nuclear distribution protein nudE-like 1 (NDEL1).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Nuclear distribution protein nudE-like 1 (NDEL1).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nuclear distribution protein nudE-like 1 (NDEL1).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Nuclear distribution protein nudE-like 1 (NDEL1).	[15]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Nuclear distribution protein nudE-like 1 (NDEL1).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Nuclear distribution protein nudE-like 1 (NDEL1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Nuclear distribution protein nudE-like 1 (NDEL1).	[19]

3 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 Nuclear distribution protein nudE-like 1 (NDEL1).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Nuclear distribution protein nudE-like 1 (NDEL1).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Nuclear distribution protein nudE-like 1 (NDEL1).	[18]

References

• [1] No association of polymorphisms in the CDK5, NDEL1, and LIS1 with autism in Chinese Han population.Psychiatry Res. 2011 Dec 30;190(2-3):369-71. doi: 10.1016/j.psychres.2011.08.004. Epub 2011 Sep 3.
• [2] Gene expression alterations related to mania and psychosis in peripheral blood of patients with a first episode of psychosis.Transl Psychiatry. 2016 Oct 4;6(10):e908. doi: 10.1038/tp.2016.159.
• [3] Oligopeptidases activity in bipolar disorder: Ndel1 and angiotensin I converting enzyme.J Affect Disord. 2019 Feb 1;244:67-70. doi: 10.1016/j.jad.2018.10.001. Epub 2018 Oct 6.
• [4] Depression, Cytokine, and Cytokine by Treatment Interactions Modulate Gene Expression in Antipsychotic Nave First Episode Psychosis.Mol Neurobiol. 2016 Oct;53(8):5701-9. doi: 10.1007/s12035-015-9489-3. Epub 2015 Oct 22.
• [5] The iridocyclitis of early onset pauciarticular juvenile rheumatoid arthritis: outcome in immunogenetically characterized patients.J Rheumatol. 1992 Jan;19(1):160-3.
• [6] NFAT1-Mediated Regulation of NDEL1 Promotes Growth and Invasion of Glioma Stem-like Cells.Cancer Res. 2019 May 15;79(10):2593-2603. doi: 10.1158/0008-5472.CAN-18-3297. Epub 2019 Apr 2.
• [7] Expression profiles of ndel1a and ndel1b, two orthologs of the NudE-Like gene, in the zebrafish.Gene Expr Patterns. 2007 Jun;7(6):672-9. doi: 10.1016/j.modgep.2007.03.003. Epub 2007 Mar 30.
• [8] Status epilepticus stimulates NDEL1 expression via the CREB/CRE pathway in the adult mouse brain.Neuroscience. 2016 Sep 7;331:1-12. doi: 10.1016/j.neuroscience.2016.06.010. Epub 2016 Jun 11.
• [9] NDE1 and NDEL1 from genes to (mal)functions: parallel but distinct roles impacting on neurodevelopmental disorders and psychiatric illness.Cell Mol Life Sci. 2017 Apr;74(7):1191-1210. doi: 10.1007/s00018-016-2395-7. Epub 2016 Oct 14.
• [10] HLA-DQA1*0101 haplotypes and disease outcome in early onset pauciarticular juvenile rheumatoid arthritis.J Rheumatol. 1991 Jun;18(6):874-9.
• [11] Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets.Arthritis Rheum. 2009 Jul;60(7):2113-23. doi: 10.1002/art.24534.
• [12] 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.
• [13] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [14] 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.
• [15] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [16] 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.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.
• [19] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.