Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ6O1IC)

• DOT Name: Casein kinase I isoform alpha (CSNK1A1)
• Synonyms: CKI-alpha; EC 2.7.11.1; CK1
• Gene Name: CSNK1A1
• UniProt ID: KC1A_HUMAN
• PDB ID: 5FQD; 6GZD; 7WTT
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MASSSGSKAEFIVGGKYKLVRKIGSGSFGDIYLAINITNGEEVAVKLESQKARHPQLLYE
  SKLYKILQGGVGIPHIRWYGQEKDYNVLVMDLLGPSLEDLFNFCSRRFTMKTVLMLADQM
  ISRIEYVHTKNFIHRDIKPDNFLMGIGRHCNKLFLIDFGLAKKYRDNRTRQHIPYREDKN
  LTGTARYASINAHLGIEQSRRDDMESLGYVLMYFNRTSLPWQGLKAATKKQKYEKISEKK
  MSTPVEVLCKGFPAEFAMYLNYCRGLRFEEAPDYMYLRQLFRILFRTLNHQYDYTFDWTM
  LKQKAAQQAASSSGQGQQAQTPTGKQTDKTKSNMKGF
• Function: Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. It can phosphorylate a large number of proteins. Participates in Wnt signaling. Phosphorylates CTNNB1 at 'Ser-45'. May phosphorylate PER1 and PER2. May play a role in segregating chromosomes during mitosis. May play a role in keratin cytoskeleton disassembly and thereby, it may regulate epithelial cell migration. Acts as a positive regulator of mTORC1 and mTORC2 signaling in response to nutrients by mediating phosphorylation of DEPTOR inhibitor. Acts as an inhibitor of NLRP3 inflammasome assembly by mediating phosphorylation of NLRP3.
• KEGG Pathway:
  Wnt sig.ling pathway (hsa04310)
  Hedgehog sig.ling pathway (hsa04340)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Human papillomavirus infection (hsa05165)
  Breast cancer (hsa05224)
  Hepatocellular carcinoma (hsa05225)
  Gastric cancer (hsa05226)
• Reactome Pathway:
  Beta-catenin phosphorylation cascade (R-HSA-196299)
  Disassembly of the destruction complex and recruitment of AXIN to the membrane (R-HSA-4641262)
  Signaling by GSK3beta mutants (R-HSA-5339716)
  CTNNB1 S33 mutants aren't phosphorylated (R-HSA-5358747)
  CTNNB1 S37 mutants aren't phosphorylated (R-HSA-5358749)
  CTNNB1 S45 mutants aren't phosphorylated (R-HSA-5358751)
  CTNNB1 T41 mutants aren't phosphorylated (R-HSA-5358752)
  APC truncation mutants have impaired AXIN binding (R-HSA-5467337)
  AXIN missense mutants destabilize the destruction complex (R-HSA-5467340)
  Truncations of AMER1 destabilize the destruction complex (R-HSA-5467348)
  Degradation of GLI2 by the proteasome (R-HSA-5610783)
  GLI3 is processed to GLI3R by the proteasome (R-HSA-5610785)
  Activation of SMO (R-HSA-5635838)
  Maturation of nucleoprotein (R-HSA-9694631)
  Degradation of beta-catenin by the destruction complex (R-HSA-195253)

Molecular Interaction Atlas (MIA) of This DOT

19 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 Casein kinase I isoform alpha (CSNK1A1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Casein kinase I isoform alpha (CSNK1A1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Casein kinase I isoform alpha (CSNK1A1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Casein kinase I isoform alpha (CSNK1A1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Casein kinase I isoform alpha (CSNK1A1).	[5]
Marinol	DM70IK5	Approved	Marinol increases the expression of Casein kinase I isoform alpha (CSNK1A1).	[6]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Casein kinase I isoform alpha (CSNK1A1).	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Casein kinase I isoform alpha (CSNK1A1).	[8]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Casein kinase I isoform alpha (CSNK1A1).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Casein kinase I isoform alpha (CSNK1A1).	[10]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Casein kinase I isoform alpha (CSNK1A1).	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Casein kinase I isoform alpha (CSNK1A1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Casein kinase I isoform alpha (CSNK1A1).	[12]
CKI-7	DMV0RFU	Preclinical	CKI-7 decreases the activity of Casein kinase I isoform alpha (CSNK1A1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Casein kinase I isoform alpha (CSNK1A1).	[14]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Casein kinase I isoform alpha (CSNK1A1).	[15]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Casein kinase I isoform alpha (CSNK1A1).	[16]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone affects the splicing of Casein kinase I isoform alpha (CSNK1A1).	[17]
Mepacrine	DMU8L7C	Investigative	Mepacrine increases the expression of Casein kinase I isoform alpha (CSNK1A1).	[18]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [7] 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.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [9] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] 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.
• [13] Casein kinase I attenuates tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by regulating the recruitment of fas-associated death domain and procaspase-8 to the death-inducing signaling complex. Cancer Res. 2004 Nov 1;64(21):8036-44. doi: 10.1158/0008-5472.CAN-04-0762.
• [14] Bisphenol A triggers the malignancy of nasopharyngeal carcinoma cells via activation of Wnt/-catenin pathway. Toxicol In Vitro. 2020 Aug;66:104881. doi: 10.1016/j.tiv.2020.104881. Epub 2020 Apr 30.
• [15] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [16] 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.
• [17] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.
• [18] Nanoquinacrine caused apoptosis in oral cancer stem cells by disrupting the interaction between GLI1 and catenin through activation of GSK3. Toxicol Appl Pharmacol. 2017 Sep 1;330:53-64. doi: 10.1016/j.taap.2017.07.008. Epub 2017 Jul 15.