Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2N8Q17)

• DOT Name: Nuclear distribution protein nudE homolog 1 (NDE1)
• Synonyms: NudE
• Gene Name: NDE1
• Related Disease:
  Aortic aneurysm, familial thoracic 4
  Lissencephaly 4
  Alzheimer disease
  Anxiety disorder
  Breast neoplasm
  Depression
  Epithelial ovarian cancer
  HIV infectious disease
  Mental disorder
  Neoplasm
  Parkinson disease
  Psychotic disorder
  Lissencephaly spectrum disorders
  Neurodevelopmental disorder
  Hydranencephaly
  Microlissencephaly
  NDE1-related microhydranencephaly
  Classic lissencephaly
  Colorectal carcinoma
  Isolated congenital microcephaly
  Nervous system disease
• UniProt ID: NDE1_HUMAN
• PDB ID: 7E1T
• Pfam ID: PF04880
• Sequence:
  MEDSGKTFSSEEEEANYWKDLAMTYKQRAENTQEELREFQEGSREYEAELETQLQQIETR
  NRDLLSENNRLRMELETIKEKFEVQHSEGYRQISALEDDLAQTKAIKDQLQKYIRELEQA
  NDDLERAKRATIMSLEDFEQRLNQAIERNAFLESELDEKENLLESVQRLKDEARDLRQEL
  AVQQKQEKPRTPMPSSVEAERTDTAVQATGSVPSTPIAHRGPSSSLNTPGSFRRGLDDST
  GGTPLTPAARISALNIVGDLLRKVGALESKLASCRNLVYDQSPNRTGGPASGRSSKNRDG
  GERRPSSTSVPLGDKGLDTSCRWLSKSTTRSSSSC
• Function: Required for centrosome duplication and formation and function of the mitotic spindle. Essential for the development of the cerebral cortex. May regulate the production of neurons by controlling the orientation of the mitotic spindle during division of cortical neuronal progenitors of the proliferative ventricular zone of the brain. Orientation of the division plane perpendicular to the layers of the cortex gives rise to two proliferative neuronal progenitors whereas parallel orientation of the division plane yields one proliferative neuronal progenitor and a post-mitotic neuron. A premature shift towards a neuronal fate within the progenitor population may result in an overall reduction in the final number of neurons and an increase in the number of neurons in the deeper layers of the cortex.
• Tissue Specificity: Expressed in the neuroepithelium throughout the developing brain, including the cerebral cortex and cerebellum.
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  RHO GTPases Activate Formins (R-HSA-5663220)
  Mitotic Prometaphase (R-HSA-68877)
  AURKA Activation by TPX2 (R-HSA-8854518)
  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

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aortic aneurysm, familial thoracic 4	DISLIFJ4	Definitive	CausalMutation	[1]
Lissencephaly 4	DISFQY9L	Definitive	Autosomal recessive	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Anxiety disorder	DISBI2BT	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[5]
Depression	DIS3XJ69	Strong	Biomarker	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[6]
HIV infectious disease	DISO97HC	Strong	Biomarker	[3]
Mental disorder	DIS3J5R8	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Parkinson disease	DISQVHKL	Strong	Biomarker	[8]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[9]
Lissencephaly spectrum disorders	DISBCZL7	moderate	Genetic Variation	[10]
Neurodevelopmental disorder	DIS372XH	moderate	Biomarker	[7]
Hydranencephaly	DISE02PO	Supportive	Autosomal recessive	[10]
Microlissencephaly	DISUCKNT	Supportive	Autosomal recessive	[2]
NDE1-related microhydranencephaly	DISDVU5W	Supportive	Autosomal recessive	[10]
Classic lissencephaly	DISR8S3S	Limited	Biomarker	[11]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[12]
Isolated congenital microcephaly	DISUXHZ6	Limited	Genetic Variation	[13]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[11]

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 Nuclear distribution protein nudE homolog 1 (NDE1).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Nuclear distribution protein nudE homolog 1 (NDE1).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Nuclear distribution protein nudE homolog 1 (NDE1).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nuclear distribution protein nudE homolog 1 (NDE1).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Nuclear distribution protein nudE homolog 1 (NDE1).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Nuclear distribution protein nudE homolog 1 (NDE1).	[19]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Nuclear distribution protein nudE homolog 1 (NDE1).	[20]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Nuclear distribution protein nudE homolog 1 (NDE1).	[21]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Nuclear distribution protein nudE homolog 1 (NDE1).	[21]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Nuclear distribution protein nudE homolog 1 (NDE1).	[22]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Nuclear distribution protein nudE homolog 1 (NDE1).	[23]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Nuclear distribution protein nudE homolog 1 (NDE1).	[24]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of Nuclear distribution protein nudE homolog 1 (NDE1).	[25]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Nuclear distribution protein nudE homolog 1 (NDE1).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Nuclear distribution protein nudE homolog 1 (NDE1).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Nuclear distribution protein nudE homolog 1 (NDE1).	[27]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Nuclear distribution protein nudE homolog 1 (NDE1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Nuclear distribution protein nudE homolog 1 (NDE1).	[28]

References

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• [3] Profile of neuronal exosomes in HIV cognitive impairment exposes sex differences.AIDS. 2019 Sep 1;33(11):1683-1692. doi: 10.1097/QAD.0000000000002272.
• [4] Characteristics of new depression diagnoses in patients with and without prior chronic opioid use.J Affect Disord. 2017 Mar 1;210:125-129. doi: 10.1016/j.jad.2016.12.027. Epub 2016 Dec 21.
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• [10] Novel NDE1 homozygous mutation resulting in microhydranencephaly and not microlyssencephaly. Neurogenetics. 2012 Aug;13(3):189-94. doi: 10.1007/s10048-012-0326-9. Epub 2012 Apr 15.
• [11] Mutations in cytoplasmic dynein and its regulators cause malformations of cortical development and neurodegenerative diseases.Biochem Soc Trans. 2013 Dec;41(6):1605-12. doi: 10.1042/BST20130188.
• [12] High prevalence of fatty acid synthase expression in colorectal cancers in Middle Eastern patients and its potential role as a therapeutic target.Am J Gastroenterol. 2009 Jul;104(7):1790-801. doi: 10.1038/ajg.2009.230. Epub 2009 Jun 2.
• [13] Phenotypic spectrum of NDE1-related disorders: from microlissencephaly to microhydranencephaly. Am J Med Genet A. 2019 Mar;179(3):494-497. doi: 10.1002/ajmg.a.61035. Epub 2019 Jan 13.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
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• [16] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [20] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [21] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [22] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [23] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [24] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [25] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [26] 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.
• [27] 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.
• [28] 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.