Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT57ECW9)

• DOT Name: Neuronal growth regulator 1 (NEGR1)
• Synonyms: IgLON family member 4
• Gene Name: NEGR1
• Related Disease:
  Intellectual disability
  Advanced cancer
  Autism spectrum disorder
  Depression
  Major depressive disorder
  MASS syndrome
  Mood disorder
  Neoplasm
  Niemann-Pick disease, type C1
  Prion disease
  Eating disorder
  Niemann-Pick disease type C
  Niemann-Pick disease, type C2
  Asthma
  Autism
  Mental disorder
  Neuroblastoma
  Non-insulin dependent diabetes
  Schizophrenia
  Type-1/2 diabetes
• UniProt ID: NEGR1_HUMAN
• PDB ID: 6DLD; 6U6T
• Pfam ID: PF13927 ; PF07686
• Sequence:
  MDMMLLVQGACCSNQWLAAVLLSLCCLLPSCLPAGQSVDFPWAAVDNMMVRKGDTAVLRC
  YLEDGASKGAWLNRSSIIFAGGDKWSVDPRVSISTLNKRDYSLQIQNVDVTDDGPYTCSV
  QTQHTPRTMQVHLTVQVPPKIYDISNDMTVNEGTNVTLTCLATGKPEPSISWRHISPSAK
  PFENGQYLDIYGITRDQAGEYECSAENDVSFPDVRKVKVVVNFAPTIQEIKSGTVTPGRS
  GLIRCEGAGVPPPAFEWYKGEKKLFNGQQGIIIQNFSTRSILTVTNVTQEHFGNYTCVAA
  NKLGTTNASLPLNPPSTAQYGITGSADVLFSCWYLVLTLSSFTSIFYLKNAILQ
• Function: May be involved in cell-adhesion. May function as a trans-neural growth-promoting factor in regenerative axon sprouting in the mammalian brain.
• KEGG Pathway: Cell adhesion molecules (hsa04514)
• Reactome Pathway: Post-translational modification (R-HSA-163125)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[3]
Depression	DIS3XJ69	Strong	Biomarker	[4]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[5]
MASS syndrome	DISI3721	Strong	Biomarker	[6]
Mood disorder	DISLVMWO	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Niemann-Pick disease, type C1	DIS9HUE3	Strong	Genetic Variation	[7]
Prion disease	DISOUMB0	Strong	Biomarker	[8]
Eating disorder	DISVGXN0	moderate	Biomarker	[9]
Niemann-Pick disease type C	DIS492ZO	moderate	Biomarker	[10]
Niemann-Pick disease, type C2	DISLYVZZ	moderate	Biomarker	[10]
Asthma	DISW9QNS	Limited	Biomarker	[11]
Autism	DISV4V1Z	Limited	Biomarker	[12]
Mental disorder	DIS3J5R8	Limited	Biomarker	[12]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[13]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[14]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[15]
Type-1/2 diabetes	DISIUHAP	Limited	Genetic Variation	[16]

11 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 Neuronal growth regulator 1 (NEGR1).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Neuronal growth regulator 1 (NEGR1).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Neuronal growth regulator 1 (NEGR1).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Neuronal growth regulator 1 (NEGR1).	[21]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Neuronal growth regulator 1 (NEGR1).	[23]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Neuronal growth regulator 1 (NEGR1).	[24]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Neuronal growth regulator 1 (NEGR1).	[24]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Neuronal growth regulator 1 (NEGR1).	[25]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Neuronal growth regulator 1 (NEGR1).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Neuronal growth regulator 1 (NEGR1).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Neuronal growth regulator 1 (NEGR1).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Neuronal growth regulator 1 (NEGR1).	[18]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Neuronal growth regulator 1 (NEGR1).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Neuronal growth regulator 1 (NEGR1).	[26]

References

• [1] Neuronal Growth and Behavioral Alterations in Mice Deficient for the Psychiatric Disease-Associated Negr1 Gene.Front Mol Neurosci. 2018 Feb 9;11:30. doi: 10.3389/fnmol.2018.00030. eCollection 2018.
• [2] The IgLON family in epithelial ovarian cancer: expression profiles and clinicopathologic correlates.Clin Cancer Res. 2005 Aug 15;11(16):5764-8. doi: 10.1158/1078-0432.CCR-04-2388.
• [3] NEGR1 and FGFR2 cooperatively regulate cortical development and core behaviours related to autism disorders in mice.Brain. 2018 Sep 1;141(9):2772-2794. doi: 10.1093/brain/awy190.
• [4] Negr1 controls adult hippocampal neurogenesis and affective behaviors.Mol Psychiatry. 2019 Aug;24(8):1189-1205. doi: 10.1038/s41380-018-0347-3. Epub 2019 Jan 16.
• [5] Identification of common genetic risk variants for autism spectrum disorder.Nat Genet. 2019 Mar;51(3):431-444. doi: 10.1038/s41588-019-0344-8. Epub 2019 Feb 25.
• [6] Functional inactivation of the genome-wide association study obesity gene neuronal growth regulator 1 in mice causes a body mass phenotype.PLoS One. 2012;7(7):e41537. doi: 10.1371/journal.pone.0041537. Epub 2012 Jul 23.
• [7] Association between obesity and polymorphisms in SEC16B, TMEM18, GNPDA2, BDNF, FAIM2 and MC4R in a Japanese population.J Hum Genet. 2009 Dec;54(12):727-31. doi: 10.1038/jhg.2009.106. Epub 2009 Oct 23.
• [8] Proteomic Screen of Brain Glycoproteome Reveals Prion Specific Marker of Pathogenesis.Proteomics. 2018 Jan;18(1). doi: 10.1002/pmic.201700296.
• [9] Impact of NEGR1 genetic variability on psychological traits of patients with eating disorders.Pharmacogenomics J. 2015 Jun;15(3):278-83. doi: 10.1038/tpj.2014.53. Epub 2014 Sep 23.
• [10] The new obesity-associated protein, neuronal growth regulator 1 (NEGR1), is implicated in Niemann-Pick disease Type C (NPC2)-mediated cholesterol trafficking.Biochem Biophys Res Commun. 2017 Jan 22;482(4):1367-1374. doi: 10.1016/j.bbrc.2016.12.043. Epub 2016 Dec 9.
• [11] Analyses of shared genetic factors between asthma and obesity in children.J Allergy Clin Immunol. 2010 Sep;126(3):631-7.e1-8. doi: 10.1016/j.jaci.2010.06.030.
• [12] Neural cell adhesion molecule Negr1 deficiency in mouse results in structural brain endophenotypes and behavioral deviations related to psychiatric disorders.Sci Rep. 2019 Apr 1;9(1):5457. doi: 10.1038/s41598-019-41991-8.
• [13] Aberrations of NEGR1 on 1p31 and MYEOV on 11q13 in neuroblastoma.Cancer Sci. 2011 Sep;102(9):1645-50. doi: 10.1111/j.1349-7006.2011.01995.x. Epub 2011 Jul 3.
• [14] Associations of genetic variants in/near body mass index-associated genes with type 2 diabetes: a systematic meta-analysis.Clin Endocrinol (Oxf). 2014 Nov;81(5):702-10. doi: 10.1111/cen.12428. Epub 2014 Mar 13.
• [15] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [16] Novel genomic signals of recent selection in an Ethiopian population.Eur J Hum Genet. 2015 Aug;23(8):1085-92. doi: 10.1038/ejhg.2014.233. Epub 2014 Nov 5.
• [17] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [18] 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.
• [19] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [20] 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.
• [21] 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.
• [22] Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood. Epigenetics. 2014 May;9(5):774-82. doi: 10.4161/epi.28153. Epub 2014 Feb 13.
• [23] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [24] 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.
• [25] 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.
• [26] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [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] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.