Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7RNPEY)

• DOT Name: Contactin-1 (CNTN1)
• Synonyms: Glycoprotein gp135; Neural cell surface protein F3
• Gene Name: CNTN1
• Related Disease:
  Compton-North congenital myopathy
  Schizophrenia
• UniProt ID: CNTN1_HUMAN
• PDB ID: 2EE2; 3S97
• Pfam ID: PF00041 ; PF07679 ; PF00047 ; PF13927
• Sequence:
  MKMWLLVSHLVIISITTCLAEFTWYRRYGHGVSEEDKGFGPIFEEQPINTIYPEESLEGK
  VSLNCRARASPFPVYKWRMNNGDVDLTSDRYSMVGGNLVINNPDKQKDAGIYYCLASNNY
  GMVRSTEATLSFGYLDPFPPEERPEVRVKEGKGMVLLCDPPYHFPDDLSYRWLLNEFPVF
  ITMDKRRFVSQTNGNLYIANVEASDKGNYSCFVSSPSITKSVFSKFIPLIPIPERTTKPY
  PADIVVQFKDVYALMGQNVTLECFALGNPVPDIRWRKVLEPMPSTAEISTSGAVLKIFNI
  QLEDEGIYECEAENIRGKDKHQARIYVQAFPEWVEHINDTEVDIGSDLYWPCVATGKPIP
  TIRWLKNGYAYHKGELRLYDVTFENAGMYQCIAENTYGAIYANAELKILALAPTFEMNPM
  KKKILAAKGGRVIIECKPKAAPKPKFSWSKGTEWLVNSSRILIWEDGSLEINNITRNDGG
  IYTCFAENNRGKANSTGTLVITDPTRIILAPINADITVGENATMQCAASFDPALDLTFVW
  SFNGYVIDFNKENIHYQRNFMLDSNGELLIRNAQLKHAGRYTCTAQTIVDNSSASADLVV
  RGPPGPPGGLRIEDIRATSVALTWSRGSDNHSPISKYTIQTKTILSDDWKDAKTDPPIIE
  GNMEAARAVDLIPWMEYEFRVVATNTLGRGEPSIPSNRIKTDGAAPNVAPSDVGGGGGRN
  RELTITWAPLSREYHYGNNFGYIVAFKPFDGEEWKKVTVTNPDTGRYVHKDETMSPSTAF
  QVKVKAFNNKGDGPYSLVAVINSAQDAPSEAPTEVGVKVLSSSEISVHWEHVLEKIVESY
  QIRYWAAHDKEEAANRVQVTSQEYSARLENLLPDTQYFIEVGACNSAGCGPPSDMIEAFT
  KKAPPSQPPRIISSVRSGSRYIITWDHVVALSNESTVTGYKVLYRPDGQHDGKLYSTHKH
  SIEVPIPRDGEYVVEVRAHSDGGDGVVSQVKISGAPTLSPSLLGLLLPAFGILVYLEF
• Function: Contactins mediate cell surface interactions during nervous system development. Involved in the formation of paranodal axo-glial junctions in myelinated peripheral nerves and in the signaling between axons and myelinating glial cells via its association with CNTNAP1. Participates in oligodendrocytes generation by acting as a ligand of NOTCH1. Its association with NOTCH1 promotes NOTCH1 activation through the released notch intracellular domain (NICD) and subsequent translocation to the nucleus. Interaction with TNR induces a repulsion of neurons and an inhibition of neurite outgrowth.
• Tissue Specificity: Strongly expressed in brain and in neuroblastoma and retinoblastoma cell lines. Lower levels of expression in lung, pancreas, kidney and skeletal muscle.
• KEGG Pathway: Cell adhesion molecules (hsa04514)
• Reactome Pathway:
  NOTCH2 Activation and Transmission of Signal to the Nucleus (R-HSA-2979096)
  L1CAM interactions (R-HSA-373760)
  Neurofascin interactions (R-HSA-447043)
  Activated NOTCH1 Transmits Signal to the Nucleus (R-HSA-2122948)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Compton-North congenital myopathy	DISQ34I5	Strong	Autosomal recessive	[1]
Schizophrenia	DISSRV2N	No Known	Unknown	[2]

18 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 Contactin-1 (CNTN1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Contactin-1 (CNTN1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Contactin-1 (CNTN1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Contactin-1 (CNTN1).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Contactin-1 (CNTN1).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Contactin-1 (CNTN1).	[8]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Contactin-1 (CNTN1).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Contactin-1 (CNTN1).	[10]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Contactin-1 (CNTN1).	[11]
Tubocurarine	DMBZIVP	Approved	Tubocurarine decreases the expression of Contactin-1 (CNTN1).	[12]
Mecamylamine	DMGQFYB	Approved	Mecamylamine increases the expression of Contactin-1 (CNTN1).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Contactin-1 (CNTN1).	[10]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Contactin-1 (CNTN1).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Contactin-1 (CNTN1).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Contactin-1 (CNTN1).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Contactin-1 (CNTN1).	[16]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Contactin-1 (CNTN1).	[17]
BRN-3548355	DM4KXT0	Investigative	BRN-3548355 increases the expression of Contactin-1 (CNTN1).	[18]

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 Contactin-1 (CNTN1).	[13]

References

• [1] Mutations in contactin-1, a neural adhesion and neuromuscular junction protein, cause a familial form of lethal congenital myopathy. Am J Hum Genet. 2008 Dec;83(6):714-24. doi: 10.1016/j.ajhg.2008.10.022. Epub 2008 Nov 20.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [8] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] 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.
• [11] Nicotine modulates the expression of a diverse set of genes in the neuronal SH-SY5Y cell line. J Biol Chem. 2003 May 2;278(18):15633-40.
• [12] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [17] 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.
• [18] 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) enhances invasiveness of lung cancer cells by up-regulating contactin-1 via the alpha7 nicotinic acetylcholine receptor/ERK signaling pathway. Chem Biol Interact. 2009 May 15;179(2-3):154-9. doi: 10.1016/j.cbi.2008.10.042. Epub 2008 Nov 5.