Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4T73GG)

• DOT Name: Cytoskeleton-associated protein 2-like (CKAP2L)
• Synonyms: Radial fiber and mitotic spindle protein; Radmis
• Gene Name: CKAP2L
• Related Disease:
  Filippi syndrome
  Hepatocellular carcinoma
  Advanced cancer
  Bipolar disorder
  Leukocyte adhesion deficiency type 1
  Lung adenocarcinoma
  Polydactyly
  Syndactyly
• UniProt ID: CKP2L_HUMAN
• Pfam ID: PF15297
• Sequence:
  MVGPGPTAAAAVEERQRKLQEYLAAKGKLKSQNTKPYLKSKNNCQNQPPSKSTIRPKNDV
  TNHVVLPVKPKRSISIKLQPRPPNTAGSQKPKLEPPKLLGKRLTSECVSSNPYSKPSSKS
  FQQCEAGSSTTGELSRKPVGSLNIEQLKTTKQQLTDQGNGKCIDFMNNIHVENESLDNFL
  KETNKENLLDILTEPERKPDPKLYTRSKPKTDSYNQTKNSLVPKQALGKSSVNSAVLKDR
  VNKQFVGETQSRTFPVKSQQLSRGADLARPGVKPSRTVPSHFIRTLSKVQSSKKPVVKNI
  KDIKVNRSQYERPNETKIRSYPVTEQRVKHTKPRTYPSLLQGEYNNRHPNIKQDQKSSQV
  CIPQTSCVLQKSKAISQRPNLTVGRFNSAIPSTPSIRPNGTSGNKHNNNGFQQKAQTLDS
  KLKKAVPQNHFLNKTAPKTQADVTTVNGTQTNPNIKKKATAEDRRKQLEEWQKSKGKTYK
  RPPMELKTKRKVIKEMNISFWKSIEKEEEEKKAQLELSSKINNTLTECLNLIEGGVPSNE
  ILNILSSIPEAEKFAKFWICKAKLLASKGTFDVIGLYEEAIKNGATPIQELRKVVLNILQ
  DSNRTTEGITSDSLVAETSITSVEELAKKMESVKSCLSPKEREQVTATPRIAKAEQHNYP
  GIKLQIGPIPRINGMPEVQDMKFITPVRRSSRIERAVSRYPEMLQEHDLVVASLDELLEV
  EETKCFIFRRNEALPVTLGFQTPES
• Function: Microtubule-associated protein required for mitotic spindle formation and cell-cycle progression in neural progenitor cells.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Filippi syndrome	DISFTDQH	Definitive	Autosomal recessive	[1]
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[4]
Leukocyte adhesion deficiency type 1	DISA1J7W	Strong	Altered Expression	[3]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[3]
Polydactyly	DIS25BMZ	Strong	Biomarker	[5]
Syndactyly	DISZK2BT	moderate	Genetic Variation	[6]

19 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 Cytoskeleton-associated protein 2-like (CKAP2L).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cytoskeleton-associated protein 2-like (CKAP2L).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytoskeleton-associated protein 2-like (CKAP2L).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cytoskeleton-associated protein 2-like (CKAP2L).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cytoskeleton-associated protein 2-like (CKAP2L).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Cytoskeleton-associated protein 2-like (CKAP2L).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Cytoskeleton-associated protein 2-like (CKAP2L).	[12]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Cytoskeleton-associated protein 2-like (CKAP2L).	[13]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Cytoskeleton-associated protein 2-like (CKAP2L).	[14]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Cytoskeleton-associated protein 2-like (CKAP2L).	[15]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of Cytoskeleton-associated protein 2-like (CKAP2L).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Cytoskeleton-associated protein 2-like (CKAP2L).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cytoskeleton-associated protein 2-like (CKAP2L).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Cytoskeleton-associated protein 2-like (CKAP2L).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Cytoskeleton-associated protein 2-like (CKAP2L).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cytoskeleton-associated protein 2-like (CKAP2L).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cytoskeleton-associated protein 2-like (CKAP2L).	[22]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Cytoskeleton-associated protein 2-like (CKAP2L).	[23]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Cytoskeleton-associated protein 2-like (CKAP2L).	[24]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] 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.
• [3] Up-regulation of CKAP2L expression promotes lung adenocarcinoma invasion and is associated with poor prognosis.Onco Targets Ther. 2019 Feb 12;12:1171-1180. doi: 10.2147/OTT.S182242. eCollection 2019.
• [4] Reducing the rate and duration of Re-ADMISsions among patients with unipolar disorder and bipolar disorder using smartphone-based monitoring and treatment - the RADMIS trials: study protocol for two randomized controlled trials.Trials. 2017 Jun 15;18(1):277. doi: 10.1186/s13063-017-2015-3.
• [5] Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome. Am J Hum Genet. 2014 Nov 6;95(5):622-32. doi: 10.1016/j.ajhg.2014.10.008. Epub 2014 Nov 6.
• [6] Mosaic CREBBP mutation causes overlapping clinical features of Rubinstein-Taybi and Filippi syndromes.Eur J Hum Genet. 2016 Aug;24(9):1363-6. doi: 10.1038/ejhg.2016.14. Epub 2016 Mar 9.
• [7] 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.
• [8] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [9] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [10] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [13] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [14] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [15] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [16] Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012 Oct;11(10):2138-48. doi: 10.1158/1535-7163.MCT-12-0562. Epub 2012 Aug 6.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Gene expression changes in human prostate carcinoma cells exposed to genotoxic and nongenotoxic aryl hydrocarbon receptor ligands. Toxicol Lett. 2011 Oct 10;206(2):178-88.
• [19] 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.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] 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.
• [22] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [23] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [24] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.