Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8OO6ZE)

• DOT Name: Neurocan core protein (NCAN)
• Synonyms: Chondroitin sulfate proteoglycan 3
• Gene Name: NCAN
• Related Disease:
  Adrenoleukodystrophy
  Advanced cancer
  Alcohol use disorder
  Alcoholic cirrhosis of liver
  Alcoholic liver diseases
  Hepatitis C virus infection
  Neoplasm
  Neuroblastoma
  Attention deficit hyperactivity disorder
  Bipolar depression
  Bipolar disorder
  Brain disease
  Fatty liver disease
  Major depressive disorder
  Multiple sclerosis
  Nervous system disease
  Urinary bladder cancer
  Urinary bladder neoplasm
  Hepatocellular carcinoma
  Schizophrenia
  Hepatitis
• UniProt ID: NCAN_HUMAN
• Pfam ID: PF00008 ; PF00059 ; PF00084 ; PF07686 ; PF00193
• Sequence:
  MGAPFVWALGLLMLQMLLFVAGEQGTQDITDASERGLHMQKLGSGSVQAALAELVALPCL
  FTLQPRPSAARDAPRIKWTKVRTASGQRQDLPILVAKDNVVRVAKSWQGRVSLPSYPRRR
  ANATLLLGPLRASDSGLYRCQVVRGIEDEQDLVPLEVTGVVFHYRSARDRYALTFAEAQE
  ACRLSSAIIAAPRHLQAAFEDGFDNCDAGWLSDRTVRYPITQSRPGCYGDRSSLPGVRSY
  GRRNPQELYDVYCFARELGGEVFYVGPARRLTLAGARAQCRRQGAALASVGQLHLAWHEG
  LDQCDPGWLADGSVRYPIQTPRRRCGGPAPGVRTVYRFANRTGFPSPAERFDAYCFRAHH
  PTSQHGDLETPSSGDEGEILSAEGPPVRELEPTLEEEEVVTPDFQEPLVSSGEEETLILE
  EKQESQQTLSPTPGDPMLASWPTGEVWLSTVAPSPSDMGAGTAASSHTEVAPTDPMPRRR
  GRFKGLNGRYFQQQEPEPGLQGGMEASAQPPTSEAAVNQMEPPLAMAVTEMLGSGQSRSP
  WADLTNEVDMPGAGSAGGKSSPEPWLWPPTMVPPSISGHSRAPVLELEKAEGPSARPATP
  DLFWSPLEATVSAPSPAPWEAFPVATSPDLPMMAMLRGPKEWMLPHPTPISTEANRVEAH
  GEATATAPPSPAAETKVYSLPLSLTPTGQGGEAMPTTPESPRADFRETGETSPAQVNKAE
  HSSSSPWPSVNRNVAVGFVPTETATEPTGLRGIPGSESGVFDTAESPTSGLQATVDEVQD
  PWPSVYSKGLDASSPSAPLGSPGVFLVPKVTPNLEPWVATDEGPTVNPMDSTVTPAPSDA
  SGIWEPGSQVFEEAESTTLSPQVALDTSIVTPLTTLEQGDKVGVPAMSTLGSSSSQPHPE
  PEDQVETQGTSGASVPPHQSSPLGKPAVPPGTPTAASVGESASVSSGEPTVPWDPSSTLL
  PVTLGIEDFELEVLAGSPGVESFWEEVASGEEPALPGTPMNAGAEEVHSDPCENNPCLHG
  GTCNANGTMYGCSCDQGFAGENCEIDIDDCLCSPCENGGTCIDEVNGFVCLCLPSYGGSF
  CEKDTEGCDRGWHKFQGHCYRYFAHRRAWEDAEKDCRRRSGHLTSVHSPEEHSFINSFGH
  ENTWIGLNDRIVERDFQWTDNTGLQFENWRENQPDNFFAGGEDCVVMVAHESGRWNDVPC
  NYNLPYVCKKGTVLCGPPPAVENASLIGARKAKYNVHATVRYQCNEGFAQHHVATIRCRS
  NGKWDRPQIVCTKPRRSHRMRRHHHHHQHHHQHHHHKSRKERRKHKKHPTEDWEKDEGNF
  C
• Function: May modulate neuronal adhesion and neurite growth during development by binding to neural cell adhesion molecules (NG-CAM and N-CAM). Chondroitin sulfate proteoglycan; binds to hyaluronic acid.
• Tissue Specificity: Detected in cerebrospinal fluid (at protein level) . Brain.
• Reactome Pathway:
  Chondroitin sulfate biosynthesis (R-HSA-2022870)
  Dermatan sulfate biosynthesis (R-HSA-2022923)
  CS/DS degradation (R-HSA-2024101)
  ECM proteoglycans (R-HSA-3000178)
  Defective B4GALT7 causes EDS, progeroid type (R-HSA-3560783)
  Defective B3GAT3 causes JDSSDHD (R-HSA-3560801)
  Defective CHST3 causes SEDCJD (R-HSA-3595172)
  Defective CHST14 causes EDS, musculocontractural type (R-HSA-3595174)
  Defective CHSY1 causes TPBS (R-HSA-3595177)
  L1CAM interactions (R-HSA-373760)
  NCAM1 interactions (R-HSA-419037)
  Defective B3GALT6 causes EDSP2 and SEMDJL1 (R-HSA-4420332)
  A tetrasaccharide linker sequence is required for GAG synthesis (R-HSA-1971475)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adrenoleukodystrophy	DISTUD1F	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Definitive	Altered Expression	[2]
Alcohol use disorder	DISMB65Y	Definitive	Genetic Variation	[1]
Alcoholic cirrhosis of liver	DISQ1WRT	Definitive	Genetic Variation	[1]
Alcoholic liver diseases	DISXEPHQ	Definitive	Genetic Variation	[1]
Hepatitis C virus infection	DISQ0M8R	Definitive	Genetic Variation	[1]
Neoplasm	DISZKGEW	Definitive	Altered Expression	[2]
Neuroblastoma	DISVZBI4	Definitive	Altered Expression	[2]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[3]
Bipolar depression	DISA75FU	Strong	Biomarker	[4]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[4]
Brain disease	DIS6ZC3X	Strong	Biomarker	[5]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[6]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[7]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[8]
Nervous system disease	DISJ7GGT	Strong	Genetic Variation	[9]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[10]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[10]
Hepatocellular carcinoma	DIS0J828	moderate	Genetic Variation	[11]
Schizophrenia	DISSRV2N	Disputed	Biomarker	[12]
Hepatitis	DISXXX35	Limited	Genetic Variation	[13]

6 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 Neurocan core protein (NCAN).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Neurocan core protein (NCAN).	[15]
Phenytoin	DMNOKBV	Approved	Phenytoin increases the expression of Neurocan core protein (NCAN).	[17]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Neurocan core protein (NCAN).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Neurocan core protein (NCAN).	[20]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Neurocan core protein (NCAN).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Neurocan core protein (NCAN).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Neurocan core protein (NCAN).	[19]

References

• [1] A common polymorphism in the NCAN gene is associated with hepatocellular carcinoma in alcoholic liver disease.J Hepatol. 2014 Nov;61(5):1073-9. doi: 10.1016/j.jhep.2014.06.006. Epub 2014 Jun 16.
• [2] Neurocan, an extracellular chondroitin sulfate proteoglycan, stimulates neuroblastoma cells to promote malignant phenotypes.Oncotarget. 2017 Nov 15;8(63):106296-106310. doi: 10.18632/oncotarget.22435. eCollection 2017 Dec 5.
• [3] Bipolar disorder risk alleles in children with ADHD.J Neural Transm (Vienna). 2013 Nov;120(11):1611-7. doi: 10.1007/s00702-013-1035-8. Epub 2013 May 28.
• [4] Genome-wide association study identifies 30 loci associated with bipolar disorder.Nat Genet. 2019 May;51(5):793-803. doi: 10.1038/s41588-019-0397-8. Epub 2019 May 1.
• [5] Chondroitin sulfate proteoglycans: structure-function relationship with implication in neural development and brain disorders.Biomed Res Int. 2014;2014:642798. doi: 10.1155/2014/642798. Epub 2014 May 14.
• [6] Genome-wide analysis of hepatic lipid content in extreme obesity.Acta Diabetol. 2015 Apr;52(2):373-82. doi: 10.1007/s00592-014-0654-3. Epub 2014 Sep 23.
• [7] NCAN Cross-Disorder Risk Variant Is Associated With Limbic Gray Matter Deficits in Healthy Subjects and Major Depression.Neuropsychopharmacology. 2015 Oct;40(11):2510-6. doi: 10.1038/npp.2015.86. Epub 2015 Mar 24.
• [8] Post-mortem multiple sclerosis lesion pathology is influenced by single nucleotide polymorphisms.Brain Pathol. 2020 Jan;30(1):106-119. doi: 10.1111/bpa.12760. Epub 2019 Jul 23.
• [9] Neurocan is a New Substrate for the ADAMTS12 Metalloprotease: Potential Implications in Neuropathies.Cell Physiol Biochem. 2019;52(5):1003-1016. doi: 10.33594/000000069.
• [10] Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer. Chem Res Toxicol. 2015 Jun 15;28(6):1144-55. doi: 10.1021/tx500393y. Epub 2015 Jun 3.
• [11] Independent and additive effects of PNPLA3 and TM6SF2 polymorphisms on the development of non-B, non-C hepatocellular carcinoma.J Gastroenterol. 2019 May;54(5):427-436. doi: 10.1007/s00535-018-01533-x. Epub 2018 Nov 30.
• [12] A genome-wide supported psychiatric risk variant in NCAN influences brain function and cognitive performance in healthy subjects.Hum Brain Mapp. 2015 Jan;36(1):378-90. doi: 10.1002/hbm.22635. Epub 2014 Sep 13.
• [13] Genetic variation at NCAN locus is associated with inflammation and fibrosis in non-alcoholic fatty liver disease in morbid obesity.Hum Hered. 2013;75(1):34-43. doi: 10.1159/000346195. Epub 2013 Apr 10.
• [14] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [15] 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.
• [16] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [17] Role of phenytoin in wound healing: microarray analysis of early transcriptional responses in human dermal fibroblasts. Biochem Biophys Res Commun. 2004 Feb 13;314(3):661-6. doi: 10.1016/j.bbrc.2003.12.146.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.