Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKXR9AW)

• DOT Name: Contactin-associated protein-like 4 (CNTNAP4)
• Synonyms: Cell recognition molecule Caspr4
• Gene Name: CNTNAP4
• Related Disease:
  Hepatocellular carcinoma
  Autism spectrum disorder
  Epilepsy
  Mental disorder
  Pervasive developmental disorder
  OPTN-related open angle glaucoma
• UniProt ID: CNTP4_HUMAN
• PDB ID: 4NXQ
• Pfam ID: PF00754 ; PF02210
• Sequence:
  MGSVTGAVLKTLLLLSTQNWNRVEAGNSYDCDDPLVSALPQASFSSSSELSSSHGPGFAR
  LNRRDGAGGWSPLVSNKYQWLQIDLGERMEVTAVATQGGYGSSNWVTSYLLMFSDSGWNW
  KQYRQEDSIWGFSGNANADSVVYYRLQPSIKARFLRFIPLEWNPKGRIGMRIEVFGCAYR
  SEVVDLDGKSSLLYRFDQKSLSPIKDIISLKFKTMQSDGILLHREGPNGDHITLQLRRAR
  LFLLINSGEAKLPSTSTLVNLTLGSLLDDQHWHSVLIQRLGKQVNFTVDEHRHHFHARGE
  FNLMNLDYEISFGGIPAPGKSVSFPHRNFHGCLENLYYNGVDIIDLAKQQKPQIIAMGNV
  SFSCSQPQSMPVTFLSSRSYLALPDFSGEEEVSATFQFRTWNKAGLLLFSELQLISGGIL
  LFLSDGKLKSNLYQPGKLPSDITAGVELNDGQWHSVSLSAKKNHLSVAVDGQMASAAPLL
  GPEQIYSGGTYYFGGCPDKSFGSKCKSPLGGFQGCMRLISISGKVVDLISVQQGSLGNFS
  DLQIDSCGISDRCLPNYCEHGGECSQSWSTFHCNCTNTGYRGATCHNSIYEQSCEAYKHR
  GNTSGFYYIDSDGSGPLEPFLLYCNMTETAWTIIQHNGSDLTRVRNTNPENPYAGFFEYV
  ASMEQLQATINRAEHCEQEFTYYCKKSRLVNKQDGTPLSWWVGRTNETQTYWGGSSPDLQ
  KCTCGLEGNCIDSQYYCNCDADRNEWTNDTGLLAYKEHLPVTKIVITDTGRLHSEAAYKL
  GPLLCQGDRSFWNSASFDTEASYLHFPTFHGELSADVSFFFKTTASSGVFLENLGIADFI
  RIELRSPTVVTFSFDVGNGPFEISVQSPTHFNDNQWHHVRVERNMKEASLQVDQLTPKTQ
  PAPADGHVLLQLNSQLFVGGTATRQRGFLGCIRSLQLNGMTLDLEERAQVTPEVQPGCRG
  HCSSYGKLCRNGGKCRERPIGFFCDCTFSAYTGPFCSNEISAYFGSGSSVIYNFQENYLL
  SKNSSSHAASFHGDMKLSREMIKFSFRTTRTPSLLLFVSSFYKEYLSVIIAKNGSLQIRY
  KLNKYQEPDVVNFDFKNMADGQLHHIMINREEGVVFIEIDDNRRRQVHLSSGTEFSAVKS
  LVLGRILEHSDVDQDTALAGAQGFTGCLSAVQLSHVAPLKAALHPSHPDPVTVTGHVTES
  SCMAQPGTDATSRERTHSFADHSGTIDDREPLANAIKSDSAVIGGLIAVVIFILLCITAI
  AVRIYQQKRLYKRSEAKRSENVDSAEAVLKSELNIQNAVNENQKEYFF
• Function: Presynaptic protein involved in both dopaminergic synaptic transmission and GABAergic system, thereby participating in the structural maturation of inhibitory interneuron synapses. Involved in the dopaminergic synaptic transmission by attenuating dopamine release through a presynaptic mechanism. Also participates in the GABAergic system.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[2]
Epilepsy	DISBB28L	Strong	Biomarker	[3]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[4]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[2]
OPTN-related open angle glaucoma	DISDR98A	Limited	Genetic Variation	[5]

6 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Contactin-associated protein-like 4 (CNTNAP4).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Contactin-associated protein-like 4 (CNTNAP4).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Contactin-associated protein-like 4 (CNTNAP4).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Contactin-associated protein-like 4 (CNTNAP4).	[9]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Contactin-associated protein-like 4 (CNTNAP4).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Contactin-associated protein-like 4 (CNTNAP4).	[11]

References

• [1] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [2] Neurexin Superfamily Cell Membrane Receptor Contactin-Associated Protein Like-4 (Cntnap4) Is Involved in Neural EGFL-Like 1 (Nell-1)-Responsive Osteogenesis.J Bone Miner Res. 2018 Oct;33(10):1813-1825. doi: 10.1002/jbmr.3524. Epub 2018 Jun 29.
• [3] CNTNAP4 Impacts Epilepsy Through GABAA Receptors Regulation: Evidence From Temporal Lobe Epilepsy Patients and Mouse Models.Cereb Cortex. 2018 Oct 1;28(10):3491-3504. doi: 10.1093/cercor/bhx215.
• [4] Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission.Nature. 2014 Jul 10;511(7508):236-40. doi: 10.1038/nature13248.
• [5] Genome-wide analysis of central corneal thickness in primary open-angle glaucoma cases in the NEIGHBOR and GLAUGEN consortia.Invest Ophthalmol Vis Sci. 2012 Jul 3;53(8):4468-74. doi: 10.1167/iovs.12-9784.
• [6] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [7] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [10] 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.
• [11] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.