Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1D33T4)

• DOT Name: Alpha-internexin (INA)
• Synonyms: Alpha-Inx; 66 kDa neurofilament protein; NF-66; Neurofilament-66; Neurofilament 5
• Gene Name: INA
• Related Disease:
  Colorectal carcinoma
  Glioblastoma multiforme
  Adult glioblastoma
  Advanced cancer
  Amyotrophic lateral sclerosis type 1
  Anxiety
  Cytomegalovirus infection
  Familial amyotrophic lateral sclerosis
  Frontotemporal dementia
  Glioma
  Hereditary angioedema
  Immunodeficiency
  Metastatic malignant neoplasm
  Nervous system disease
  Neuroendocrine neoplasm
  Pancreatic neuroendocrine tumor
  Pick disease
  Plasma cell myeloma
  Primitive neuroectodermal tumor
  Schizophrenia
  Urticaria
  Myofibrillar myopathy 3
  Neoplasm
  Neuroblastoma
  Amyotrophic lateral sclerosis
  leukaemia
  Leukemia
• UniProt ID: AINX_HUMAN
• Pfam ID: PF00038 ; PF04732
• Sequence:
  MSFGSEHYLCSSSSYRKVFGDGSRLSARLSGAGGAGGFRSQSLSRSNVASSAACSSASSL
  GLGLAYRRPPASDGLDLSQAAARTNEYKIIRTNEKEQLQGLNDRFAVFIEKVHQLETQNR
  ALEAELAALRQRHAEPSRVGELFQRELRDLRAQLEEASSARSQALLERDGLAEEVQRLRA
  RCEEESRGREGAERALKAQQRDVDGATLARLDLEKKVESLLDELAFVRQVHDEEVAELLA
  TLQASSQAAAEVDVTVAKPDLTSALREIRAQYESLAAKNLQSAEEWYKSKFANLNEQAAR
  STEAIRASREEIHEYRRQLQARTIEIEGLRGANESLERQILELEERHSAEVAGYQDSIGQ
  LENDLRNTKSEMARHLREYQDLLNVKMALDIEIAAYRKLLEGEETRFSTSGLSISGLNPL
  PNPSYLLPPRILSATTSKVSSTGLSLKKEEEEEEASKVASKKTSQIGESFEEILEETVIS
  TKKTEKSNIEETTISSQKI
• Function: Class-IV neuronal intermediate filament that is able to self-assemble. It is involved in the morphogenesis of neurons. It may form an independent structural network without the involvement of other neurofilaments or it may cooperate with NEFL to form the filamentous backbone to which NEFM and NEFH attach to form the cross-bridges. May also cooperate with the neuronal intermediate filament protein PRPH to form filamentous networks.
• Tissue Specificity: Found predominantly in adult CNS.

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Definitive	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Strong	Biomarker	[5]
Anxiety	DISIJDBA	Strong	Genetic Variation	[6]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[7]
Familial amyotrophic lateral sclerosis	DISWZ9CJ	Strong	Biomarker	[5]
Frontotemporal dementia	DISKYHXL	Strong	Biomarker	[7]
Glioma	DIS5RPEH	Strong	Altered Expression	[8]
Hereditary angioedema	DIS8X53J	Strong	Biomarker	[9]
Immunodeficiency	DIS093I0	Strong	Biomarker	[10]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[11]
Nervous system disease	DISJ7GGT	Strong	Biomarker	[7]
Neuroendocrine neoplasm	DISNPLOO	Strong	Altered Expression	[12]
Pancreatic neuroendocrine tumor	DISDMPU0	Strong	Biomarker	[11]
Pick disease	DISP6X50	Strong	Biomarker	[7]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[13]
Primitive neuroectodermal tumor	DISFHXHA	Strong	Altered Expression	[11]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[14]
Urticaria	DIS9WQAI	Strong	Altered Expression	[9]
Myofibrillar myopathy 3	DISENXUL	moderate	Biomarker	[15]
Neoplasm	DISZKGEW	moderate	Altered Expression	[12]
Neuroblastoma	DISVZBI4	moderate	Altered Expression	[16]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[17]
leukaemia	DISS7D1V	Limited	Biomarker	[13]
Leukemia	DISNAKFL	Limited	Biomarker	[13]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Sulforaphane	DMQY3L0	Investigative	Alpha-internexin (INA) affects the binding of Sulforaphane.	[32]

14 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 Alpha-internexin (INA).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Alpha-internexin (INA).	[19]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Alpha-internexin (INA).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Alpha-internexin (INA).	[21]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Alpha-internexin (INA).	[22]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Alpha-internexin (INA).	[23]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Alpha-internexin (INA).	[24]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Alpha-internexin (INA).	[25]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 increases the expression of Alpha-internexin (INA).	[26]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Alpha-internexin (INA).	[28]
Mivebresib	DMCPF90	Phase 1	Mivebresib increases the expression of Alpha-internexin (INA).	[26]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Alpha-internexin (INA).	[29]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Alpha-internexin (INA).	[30]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Alpha-internexin (INA).	[31]

1 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 increases the methylation of Alpha-internexin (INA).	[27]

References

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• [3] alpha-Internexin expression identifies 1p19q codeleted gliomas.Neurology. 2009 Jan 13;72(2):156-61. doi: 10.1212/01.wnl.0000339055.64476.cb.
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• [10] Janus kinase inhibitor INCB20 has antiproliferative and apoptotic effects on human myeloma cells in vitro and in vivo.Mol Cancer Ther. 2009 Jan;8(1):26-35. doi: 10.1158/1535-7163.MCT-08-0149.
• [11] -Internexin: a novel biomarker for pancreatic neuroendocrine tumor aggressiveness.J Clin Endocrinol Metab. 2014 May;99(5):E786-95. doi: 10.1210/jc.2013-2874. Epub 2014 Jan 31.
• [12] Loss of expression and prognosis value of alpha-internexin in gastroenteropancreatic neuroendocrine neoplasm.BMC Cancer. 2018 Jun 26;18(1):691. doi: 10.1186/s12885-018-4449-8.
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• [15] Target genes of neuron-restrictive silencer factor are abnormally up-regulated in human myotilinopathy.Am J Pathol. 2007 Oct;171(4):1312-23. doi: 10.2353/ajpath.2007.070520. Epub 2007 Sep 6.
• [16] A comparative immunohistochemical analysis of small round cell tumors of childhood: utility of peripherin and alpha-internexin as markers for neuroblastomas.Appl Immunohistochem Mol Morphol. 2008 Jul;16(4):344-8. doi: 10.1097/PAI.0b013e318165fe78.
• [17] Degeneration of axons in spinal white matter in G93A mSOD1 mouse characterized by NFL and -internexin immunoreactivity.Brain Res. 2012 Jul 17;1465:90-100. doi: 10.1016/j.brainres.2012.05.018. Epub 2012 May 17.
• [18] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [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] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [23] 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.
• [24] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [25] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [26] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [27] 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.
• [28] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [29] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [30] 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.
• [31] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [32] Identification of potential protein targets of isothiocyanates by proteomics. Chem Res Toxicol. 2011 Oct 17;24(10):1735-43. doi: 10.1021/tx2002806. Epub 2011 Aug 26.