Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVN52VH)

• DOT Name: Centrosomal protein of 290 kDa (CEP290)
• Synonyms: Cep290; Bardet-Biedl syndrome 14 protein; Cancer/testis antigen 87; CT87; Nephrocystin-6; Tumor antigen se2-2
• Gene Name: CEP290
• Related Disease:
  CEP290-related ciliopathy
  Joubert syndrome 5
  Bardet-Biedl syndrome 14
  Leber congenital amaurosis 10
  Bardet biedl syndrome
  Joubert syndrome with oculorenal defect
  Leber congenital amaurosis
  Meckel syndrome
  Senior-Loken syndrome
• UniProt ID: CE290_HUMAN
• Pfam ID: PF16574
• Sequence:
  MPPNINWKEIMKVDPDDLPRQEELADNLLISLSKVEVNELKSEKQENVIHLFRITQSLMK
  MKAQEVELALEEVEKAGEEQAKFENQLKTKVMKLENELEMAQQSAGGRDTRFLRNEICQL
  EKQLEQKDRELEDMEKELEKEKKVNEQLALRNEEAENENSKLRRENKRLKKKNEQLCQDI
  IDYQKQIDSQKETLLSRRGEDSDYRSQLSKKNYELIQYLDEIQTLTEANEKIEVQNQEMR
  KNLEESVQEMEKMTDEYNRMKAIVHQTDNVIDQLKKENDHYQLQVQELTDLLKSKNEEDD
  PIMVAVNAKVEEWKLILSSKDDEIIEYQQMLHNLREKLKNAQLDADKSNVMALQQGIQER
  DSQIKMLTEQVEQYTKEMEKNTCIIEDLKNELQRNKGASTLSQQTHMKIQSTLDILKEKT
  KEAERTAELAEADAREKDKELVEALKRLKDYESGVYGLEDAVVEIKNCKNQIKIRDREIE
  ILTKEINKLELKISDFLDENEALRERVGLEPKTMIDLTEFRNSKHLKQQQYRAENQILLK
  EIESLEEERLDLKKKIRQMAQERGKRSATSGLTTEDLNLTENISQGDRISERKLDLLSLK
  NMSEAQSKNEFLSRELIEKERDLERSRTVIAKFQNKLKELVEENKQLEEGMKEILQAIKE
  MQKDPDVKGGETSLIIPSLERLVNAIESKNAEGIFDASLHLKAQVDQLTGRNEELRQELR
  ESRKEAINYSQQLAKANLKIDHLEKETSLLRQSEGSNVVFKGIDLPDGIAPSSASIINSQ
  NEYLIHLLQELENKEKKLKNLEDSLEDYNRKFAVIRHQQSLLYKEYLSEKETWKTESKTI
  KEEKRKLEDQVQQDAIKVKEYNNLLNALQMDSDEMKKILAENSRKITVLQVNEKSLIRQY
  TTLVELERQLRKENEKQKNELLSMEAEVCEKIGCLQRFKEMAIFKIAALQKVVDNSVSLS
  ELELANKQYNELTAKYRDILQKDNMLVQRTSNLEHLECENISLKEQVESINKELEITKEK
  LHTIEQAWEQETKLGNESSMDKAKKSITNSDIVSISKKITMLEMKELNERQRAEHCQKMY
  EHLRTSLKQMEERNFELETKFAELTKINLDAQKVEQMLRDELADSVSKAVSDADRQRILE
  LEKNEMELKVEVSKLREISDIARRQVEILNAQQQSRDKEVESLRMQLLDYQAQSDEKSLI
  AKLHQHNVSLQLSEATALGKLESITSKLQKMEAYNLRLEQKLDEKEQALYYARLEGRNRA
  KHLRQTIQSLRRQFSGALPLAQQEKFSKTMIQLQNDKLKIMQEMKNSQQEHRNMENKTLE
  MELKLKGLEELISTLKDTKGAQKVINWHMKIEELRLQELKLNRELVKDKEEIKYLNNIIS
  EYERTISSLEEEIVQQNKFHEERQMAWDQREVDLERQLDIFDRQQNEILNAAQKFEEATG
  SIPDPSLPLPNQLEIALRKIKENIRIILETRATCKSLEEKLKEKESALRLAEQNILSRDK
  VINELRLRLPATAEREKLIAELGRKEMEPKSHHTLKIAHQTIANMQARLNQKEEVLKKYQ
  RLLEKAREEQREIVKKHEEDLHILHHRLELQADSSLNKFKQTAWDLMKQSPTPVPTNKHF
  IRLAEMEQTVAEQDDSLSSLLVKLKKVSQDLERQREITELKVKEFENIKLQLQENHEDEV
  KKVKAEVEDLKYLLDQSQKESQCLKSELQAQKEANSRAPTTTMRNLVERLKSQLALKEKQ
  QKALSRALLELRAEMTAAAEERIISATSQKEAHLNVQQIVDRHTRELKTQVEDLNENLLK
  LKEALKTSKNRENSLTDNLNDLNNELQKKQKAYNKILREKEEIDQENDELKRQIKRLTSG
  LQGKPLTDNKQSLIEELQRKVKKLENQLEGKVEEVDLKPMKEKNAKEELIRWEEGKKWQA
  KIEGIRNKLKEKEGEVFTLTKQLNTLKDLFAKADKEKLTLQRKLKTTGMTVDQVLGIRAL
  ESEKELEELKKRNLDLENDILYMRAHQALPRDSVVEDLHLQNRYLQEKLHALEKQFSKDT
  YSKPSISGIESDDHCQREQELQKENLKLSSENIELKFQLEQANKDLPRLKNQVRDLKEMC
  EFLKKEKAEVQRKLGHVRGSGRSGKTIPELEKTIGLMKKVVEKVQRENEQLKKASGILTS
  EKMANIEQENEKLKAELEKLKAHLGHQLSMHYESKTKGTEKIIAENERLRKELKKETDAA
  EKLRIAKNNLEILNEKMTVQLEETGKRLQFAESRGPQLEGADSKSWKSIVVTRMYETKLK
  ELETDIAKKNQSITDLKQLVKEATEREQKVNKYNEDLEQQIKILKHVPEGAETEQGLKRE
  LQVLRLANHQLDKEKAELIHQIEANKDQSGAESTIPDADQLKEKIKDLETQLKMSDLEKQ
  HLKEEIKKLKKELENFDPSFFEEIEDLKYNYKEEVKKNILLEEKVKKLSEQLGVELTSPV
  AASEEFEDEEESPVNFPIY
• Function: Involved in early and late steps in cilia formation. Its association with CCP110 is required for inhibition of primary cilia formation by CCP110. May play a role in early ciliogenesis in the disappearance of centriolar satellites and in the transition of primary ciliar vesicles (PCVs) to capped ciliary vesicles (CCVs). Required for the centrosomal recruitment of RAB8A and for the targeting of centriole satellite proteins to centrosomes such as of PCM1. Required for the correct localization of ciliary and phototransduction proteins in retinal photoreceptor cells; may play a role in ciliary transport processes. Required for efficient recruitment of RAB8A to primary cilium. In the ciliary transition zone is part of the tectonic-like complex which is required for tissue-specific ciliogenesis and may regulate ciliary membrane composition. Involved in regulation of the BBSome complex integrity, specifically for presence of BBS2, BBS5 and BBS8/TTC8 in the complex, and in ciliary targeting of selected BBSome cargos. May play a role in controlling entry of the BBSome complex to cilia possibly implicating IQCB1/NPHP5. Activates ATF4-mediated transcription.
• Tissue Specificity: Ubiquitous. Expressed strongly in placenta and weakly in brain.
• Reactome Pathway:
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  Neutrophil degranulation (R-HSA-6798695)
  AURKA Activation by TPX2 (R-HSA-8854518)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
CEP290-related ciliopathy	DISUS6C6	Definitive	Autosomal recessive	[1]
Joubert syndrome 5	DIS3KWP6	Definitive	Autosomal recessive	[2]
Bardet-Biedl syndrome 14	DISJLM82	Strong	Autosomal recessive	[3]
Leber congenital amaurosis 10	DISBNBKQ	Strong	Autosomal recessive	[3]
Bardet biedl syndrome	DISTBNZW	Supportive	Autosomal recessive	[4]
Joubert syndrome with oculorenal defect	DISU0IPO	Supportive	Autosomal recessive	[5]
Leber congenital amaurosis	DISMGH8F	Supportive	Autosomal dominant	[6]
Meckel syndrome	DISXPHOY	Supportive	Autosomal recessive	[7]
Senior-Loken syndrome	DISGBSGP	Supportive	Autosomal recessive	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Centrosomal protein of 290 kDa (CEP290).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Centrosomal protein of 290 kDa (CEP290).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Centrosomal protein of 290 kDa (CEP290).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Centrosomal protein of 290 kDa (CEP290).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Centrosomal protein of 290 kDa (CEP290).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Centrosomal protein of 290 kDa (CEP290).	[14]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Centrosomal protein of 290 kDa (CEP290).	[15]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Centrosomal protein of 290 kDa (CEP290).	[16]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Centrosomal protein of 290 kDa (CEP290).	[17]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Centrosomal protein of 290 kDa (CEP290).	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Centrosomal protein of 290 kDa (CEP290).	[15]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of Centrosomal protein of 290 kDa (CEP290).	[19]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of Centrosomal protein of 290 kDa (CEP290).	[20]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] CEP290, a gene with many faces: mutation overview and presentation of CEP290base. Hum Mutat. 2010 Oct;31(10):1097-108. doi: 10.1002/humu.21337.
• [3] Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. Am J Hum Genet. 2006 Sep;79(3):556-61. doi: 10.1086/507318. Epub 2006 Jul 11.
• [4] Bardet-Biedl Syndrome Overview. 2003 Jul 14 [updated 2023 Mar 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [5] Joubert Syndrome and related disorders. Orphanet J Rare Dis. 2010 Jul 8;5:20. doi: 10.1186/1750-1172-5-20.
• [6] Review and update on the molecular basis of Leber congenital amaurosis. World J Clin Cases. 2015 Feb 16;3(2):112-24. doi: 10.12998/wjcc.v3.i2.112.
• [7] Molecular genetics and pathogenic mechanisms for the severe ciliopathies: insights into neurodevelopment and pathogenesis of neural tube defects. Mol Neurobiol. 2011 Feb;43(1):12-26. doi: 10.1007/s12035-010-8154-0. Epub 2010 Nov 27.
• [8] Senior-L?ken syndrome: a syndromic form of retinal dystrophy associated with nephronophthisis. Vision Res. 2012 Dec 15;75:88-97. doi: 10.1016/j.visres.2012.07.003. Epub 2012 Jul 20.
• [9] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [10] 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.
• [11] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] 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.
• [14] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [15] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [16] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [17] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [18] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [19] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [20] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.