Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8VCBNF)

• DOT Name: Neurofilament medium polypeptide (NEFM)
• Synonyms: NF-M; 160 kDa neurofilament protein; Neurofilament 3; Neurofilament triplet M protein
• Gene Name: NEFM
• Related Disease:
  Adenoma
  Alzheimer disease
  Amyotrophic lateral sclerosis
  Autoimmune disease
  Behcet disease
  Bipolar disorder
  Cockayne syndrome
  Congenital hypothyroidism
  Cytomegalovirus infection
  Depression
  Frontotemporal dementia
  Hypothyroidism
  Motor neurone disease
  Multiple sclerosis
  Neoplasm
  Parkinson disease
  Pick disease
  Schizophrenia
  Sciatic neuropathy
  UV-sensitive syndrome
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Endometriosis
  Neuroendocrine neoplasm
• UniProt ID: NFM_HUMAN
• Pfam ID: PF00038 ; PF04732
• Sequence:
  MSYTLDSLGNPSAYRRVTETRSSFSRVSGSPSSGFRSQSWSRGSPSTVSSSYKRSMLAPR
  LAYSSAMLSSAESSLDFSQSSSLLNGGSGPGGDYKLSRSNEKEQLQGLNDRFAGYIEKVH
  YLEQQNKEIEAEIQALRQKQASHAQLGDAYDQEIRELRATLEMVNHEKAQVQLDSDHLEE
  DIHRLKERFEEEARLRDDTEAAIRALRKDIEEASLVKVELDKKVQSLQDEVAFLRSNHEE
  EVADLLAQIQASHITVERKDYLKTDISTALKEIRSQLESHSDQNMHQAEEWFKCRYAKLT
  EAAEQNKEAIRSAKEEIAEYRRQLQSKSIELESVRGTKESLERQLSDIEERHNHDLSSYQ
  DTIQQLENELRGTKWEMARHLREYQDLLNVKMALDIEIAAYRKLLEGEETRFSTFAGSIT
  GPLYTHRPPITISSKIQKPKVEAPKLKVQHKFVEEIIEETKVEDEKSEMEEALTAITEEL
  AVSMKEEKKEAAEEKEEEPEAEEEEVAAKKSPVKATAPEVKEEEGEKEEEEGQEEEEEED
  EGAKSDQAEEGGSEKEGSSEKEEGEQEEGETEAEAEGEEAEAKEEKKVEEKSEEVATKEE
  LVADAKVEKPEKAKSPVPKSPVEEKGKSPVPKSPVEEKGKSPVPKSPVEEKGKSPVPKSP
  VEEKGKSPVSKSPVEEKAKSPVPKSPVEEAKSKAEVGKGEQKEEEEKEVKEAPKEEKVEK
  KEEKPKDVPEKKKAESPVKEEAVAEVVTITKSVKVHLEKETKEEGKPLQQEKEKEKAGGE
  GGSEEEGSDKGAKGSRKEDIAVNGEVEGKEEVEQETKEKGSGREEEKGVVTNGLDLSPAD
  EKKGGDKSEEKVVVTKTVEKITSEGGDGATKYITKSVTVTQKVEEHEETFEEKLVSTKKV
  EKVTSHAIVKEVTQSD
• Function: Neurofilaments usually contain three intermediate filament proteins: NEFL, NEFM, and NEFH which are involved in the maintenance of neuronal caliber. May additionally cooperate with the neuronal intermediate filament proteins PRPH and INA to form neuronal filamentous networks.
• KEGG Pathway:
  Amyotrophic lateral sclerosis (hsa05014)
  Pathways of neurodegeneration - multiple diseases (hsa05022)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenoma	DIS78ZEV	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Altered Expression	[3]
Autoimmune disease	DISORMTM	Strong	Biomarker	[4]
Behcet disease	DISSYMBS	Strong	Biomarker	[4]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[5]
Cockayne syndrome	DISW6GL2	Strong	Biomarker	[6]
Congenital hypothyroidism	DISL5XVU	Strong	Biomarker	[7]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[8]
Depression	DIS3XJ69	Strong	Biomarker	[5]
Frontotemporal dementia	DISKYHXL	Strong	Biomarker	[8]
Hypothyroidism	DISR0H6D	Strong	Therapeutic	[9]
Motor neurone disease	DISUHWUI	Strong	Genetic Variation	[10]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Parkinson disease	DISQVHKL	Strong	Biomarker	[13]
Pick disease	DISP6X50	Strong	Biomarker	[8]
Schizophrenia	DISSRV2N	Strong	Biomarker	[11]
Sciatic neuropathy	DISMGDKX	Strong	Biomarker	[14]
UV-sensitive syndrome	DISHCN4B	Strong	Biomarker	[6]
Advanced cancer	DISAT1Z9	Disputed	Biomarker	[15]
Breast cancer	DIS7DPX1	Disputed	Biomarker	[15]
Breast carcinoma	DIS2UE88	Disputed	Biomarker	[15]
Endometriosis	DISX1AG8	Disputed	Biomarker	[16]
Neuroendocrine neoplasm	DISNPLOO	Limited	Biomarker	[17]

23 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 Neurofilament medium polypeptide (NEFM).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Neurofilament medium polypeptide (NEFM).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Neurofilament medium polypeptide (NEFM).	[20]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Neurofilament medium polypeptide (NEFM).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Neurofilament medium polypeptide (NEFM).	[22]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Neurofilament medium polypeptide (NEFM).	[23]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Neurofilament medium polypeptide (NEFM).	[24]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Neurofilament medium polypeptide (NEFM).	[25]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Neurofilament medium polypeptide (NEFM).	[26]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Neurofilament medium polypeptide (NEFM).	[16]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Neurofilament medium polypeptide (NEFM).	[25]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Neurofilament medium polypeptide (NEFM).	[29]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Neurofilament medium polypeptide (NEFM).	[30]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Neurofilament medium polypeptide (NEFM).	[31]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Neurofilament medium polypeptide (NEFM).	[32]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Neurofilament medium polypeptide (NEFM).	[33]
Lidocaine	DML4ZOT	Approved	Lidocaine decreases the expression of Neurofilament medium polypeptide (NEFM).	[34]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Neurofilament medium polypeptide (NEFM).	[35]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Neurofilament medium polypeptide (NEFM).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Neurofilament medium polypeptide (NEFM).	[38]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Neurofilament medium polypeptide (NEFM).	[39]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Neurofilament medium polypeptide (NEFM).	[40]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Neurofilament medium polypeptide (NEFM).	[41]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Neurofilament medium polypeptide (NEFM).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Neurofilament medium polypeptide (NEFM).	[36]

References

• [1] Transcriptome Pathway Analysis of Pathological and Physiological Aldosterone-Producing Human Tissues.Hypertension. 2016 Dec;68(6):1424-1431. doi: 10.1161/HYPERTENSIONAHA.116.08033. Epub 2016 Oct 24.
• [2] Cytoskeleton derangement in brain of patients with Down syndrome, Alzheimer's disease and Pick's disease.J Neural Transm Suppl. 2003;(67):149-58. doi: 10.1007/978-3-7091-6721-2_13.
• [3] Dysregulation of human NEFM and NEFH mRNA stability by ALS-linked miRNAs.Mol Brain. 2018 Jul 20;11(1):43. doi: 10.1186/s13041-018-0386-3.
• [4] Behet Disease serum is immunoreactive to neurofilament medium which share common epitopes to bacterial HSP-65, a putative trigger.J Autoimmun. 2017 Nov;84:87-96. doi: 10.1016/j.jaut.2017.08.002. Epub 2017 Aug 24.
• [5] Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer.Mol Psychiatry. 2009 Jun;14(6):563-89. doi: 10.1038/mp.2009.2. Epub 2009 Feb 10.
• [6] Ultraviolet-sensitive syndrome cells are defective in transcription-coupled repair of cyclobutane pyrimidine dimers.DNA Repair (Amst). 2002 Aug 6;1(8):629-43. doi: 10.1016/s1568-7864(02)00056-3.
• [7] Congenital hypothyroidism is associated with intermediate filament misregulation, glutamate transporters down-regulation and MAPK activation in developing rat brain.Neurotoxicology. 2008 Nov;29(6):1092-9. doi: 10.1016/j.neuro.2008.09.004. Epub 2008 Sep 18.
• [8] Mutation analysis of patients with neuronal intermediate filament inclusion disease (NIFID).Neurobiol Aging. 2006 May;27(5):778.e1-778.e6. doi: 10.1016/j.neurobiolaging.2005.03.030. Epub 2005 Jul 7.
• [9] Regulation of neurofilament gene expression by thyroid hormone in the developing rat brain.Neuroreport. 1999 Aug 2;10(11):2361-5. doi: 10.1097/00001756-199908020-00026.
• [10] Mutations in neurofilament genes are not a significant primary cause of non-SOD1-mediated amyotrophic lateral sclerosis.Neurobiol Dis. 2006 Jan;21(1):102-9. doi: 10.1016/j.nbd.2005.06.016. Epub 2005 Aug 3.
• [11] Elevated levels of autoantibodies targeting the M1 muscarinic acetylcholine receptor and neurofilament medium in sera from subgroups of patients with schizophrenia.J Neuroimmunol. 2014 Apr 15;269(1-2):68-75. doi: 10.1016/j.jneuroim.2014.02.008. Epub 2014 Feb 25.
• [12] A newly synthesized oleanolic acid derivative inhibits the growth of osteosarcoma cells in vitro and in vivo by decreasing c-MYC-dependent glycolysis.J Cell Biochem. 2019 Jun;120(6):9264-9276. doi: 10.1002/jcb.28202. Epub 2018 Dec 14.
• [13] Mechanisms and Consequences of Dopamine Depletion-Induced Attenuation of the Spinophilin/Neurofilament Medium Interaction.Neural Plast. 2017;2017:4153076. doi: 10.1155/2017/4153076. Epub 2017 May 28.
• [14] Insulin deficiency rather than hyperglycemia accounts for impaired neurotrophic responses and nerve fiber regeneration in type 1 diabetic neuropathy.J Neuropathol Exp Neurol. 2003 Mar;62(3):260-71. doi: 10.1093/jnen/62.3.260.
• [15] Epigenetic silencing of neurofilament genes promotes an aggressive phenotype in breast cancer.Epigenetics. 2015;10(7):622-32. doi: 10.1080/15592294.2015.1050173.
• [16] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [17] Identification of novel neuroendocrine-specific tumour genes.Br J Cancer. 2008 Oct 21;99(8):1330-9. doi: 10.1038/sj.bjc.6604565. Epub 2008 Sep 30.
• [18] Valproate reversibly reduces neurite outgrowth by human SY5Y neuroblastoma cells. Brain Res. 2009 Dec 11;1302:21-33. doi: 10.1016/j.brainres.2009.09.051. Epub 2009 Sep 18.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [21] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.
• [22] 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.
• [23] Arsenic metabolites affect expression of the neurofilament and tau genes: an in-vitro study into the mechanism of arsenic neurotoxicity. Toxicol In Vitro. 2007 Sep;21(6):1104-12. doi: 10.1016/j.tiv.2007.04.007. Epub 2007 Apr 27.
• [24] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [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] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [27] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [28] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [29] 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.
• [30] Repetitive nicotine exposure leads to a more malignant and metastasis-prone phenotype of SCLC: a molecular insight into the importance of quitting smoking during treatment. Toxicol Sci. 2010 Aug;116(2):467-76. doi: 10.1093/toxsci/kfq138. Epub 2010 May 10.
• [31] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [32] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [33] Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
• [34] Lidocaine prevents breast cancer growth by targeting neuronatin to inhibit nerve fibers formation. J Toxicol Sci. 2021;46(7):329-339. doi: 10.2131/jts.46.329.
• [35] 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.
• [36] 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.
• [37] Bromodomain and extraterminal inhibition blocks tumor progression and promotes differentiation in?neuroblastoma. Surgery. 2015 Sep;158(3):819-26. doi: 10.1016/j.surg.2015.04.017. Epub 2015 Jun 9.
• [38] Proteomics and disease network associations evaluation of environmentally relevant Bisphenol A concentrations in a human 3D neural stem cell model. Front Cell Dev Biol. 2023 Aug 16;11:1236243. doi: 10.3389/fcell.2023.1236243. eCollection 2023.
• [39] 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.
• [40] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [41] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.