Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF0UXX6)

• DOT Name: Casein kinase I isoform epsilon (CSNK1E)
• Synonyms: CKI-epsilon; CKIe; EC 2.7.11.1
• Gene Name: CSNK1E
• Related Disease: Infantile spasm
• UniProt ID: KC1E_HUMAN
• PDB ID: 4HNI; 4HOK
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MELRVGNKYRLGRKIGSGSFGDIYLGANIASGEEVAIKLECVKTKHPQLHIESKFYKMMQ
  GGVGIPSIKWCGAEGDYNVMVMELLGPSLEDLFNFCSRKFSLKTVLLLADQMISRIEYIH
  SKNFIHRDVKPDNFLMGLGKKGNLVYIIDFGLAKKYRDARTHQHIPYRENKNLTGTARYA
  SINTHLGIEQSRRDDLESLGYVLMYFNLGSLPWQGLKAATKRQKYERISEKKMSTPIEVL
  CKGYPSEFSTYLNFCRSLRFDDKPDYSYLRQLFRNLFHRQGFSYDYVFDWNMLKFGAARN
  PEDVDRERREHEREERMGQLRGSATRALPPGPPTGATANRLRSAAEPVASTPASRIQPAG
  NTSPRAISRVDRERKVSMRLHRGAPANVSSSDLTGRQEVSRIPASQTSVPFDHLGK
• Function: Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates (Probable). Participates in Wnt signaling. Phosphorylates DVL1. Phosphorylates DVL2. Phosphorylates NEDD9/HEF1. Central component of the circadian clock. In balance with PP1, determines the circadian period length, through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation. Controls PER1 and PER2 nuclear transport and degradation. Inhibits cytokine-induced granuloytic differentiation.
• Tissue Specificity: Expressed in all tissues examined, including brain, heart, lung, liver, pancreas, kidney, placenta and skeletal muscle. Expressed in monocytes and lymphocytes but not in granulocytes.
• KEGG Pathway:
  FoxO sig.ling pathway (hsa04068)
  Wnt sig.ling pathway (hsa04310)
  Hedgehog sig.ling pathway (hsa04340)
  Hippo sig.ling pathway (hsa04390)
  Hippo sig.ling pathway - multiple species (hsa04392)
  Circadian rhythm (hsa04710)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway:
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)
  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)
  Circadian Clock (R-HSA-400253)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)
  AURKA Activation by TPX2 (R-HSA-8854518)
  WNT mediated activation of DVL (R-HSA-201688)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Infantile spasm	DISZSKDG	Limited	Autosomal dominant	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Amphetamine	DMSZQAK	Approved	Casein kinase I isoform epsilon (CSNK1E) increases the response to substance of Amphetamine.	[16]

12 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 epsilon (CSNK1E).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Casein kinase I isoform epsilon (CSNK1E).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Casein kinase I isoform epsilon (CSNK1E).	[4]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Casein kinase I isoform epsilon (CSNK1E).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Casein kinase I isoform epsilon (CSNK1E).	[6]
Selenium	DM25CGV	Approved	Selenium increases the expression of Casein kinase I isoform epsilon (CSNK1E).	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Casein kinase I isoform epsilon (CSNK1E).	[8]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Casein kinase I isoform epsilon (CSNK1E).	[9]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Casein kinase I isoform epsilon (CSNK1E).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Casein kinase I isoform epsilon (CSNK1E).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Casein kinase I isoform epsilon (CSNK1E).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Casein kinase I isoform epsilon (CSNK1E).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Casein kinase I isoform epsilon (CSNK1E).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Casein kinase I isoform epsilon (CSNK1E).	[14]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [5] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [6] 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.
• [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] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [9] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [10] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [11] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [15] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [16] Association between the casein kinase 1 epsilon gene region and subjective response to D-amphetamine. Neuropsychopharmacology. 2006 May;31(5):1056-63. doi: 10.1038/sj.npp.1300936.