Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNF4S77)

• DOT Name: Casein kinase I isoform delta (CSNK1D)
• Synonyms: CKI-delta; CKId; EC 2.7.11.1; Tau-protein kinase CSNK1D; EC 2.7.11.26
• Gene Name: CSNK1D
• Related Disease: Advanced sleep phase syndrome
• UniProt ID: KC1D_HUMAN
• PDB ID: 3UYS ; 3UYT ; 3UZP ; 4HGT ; 4HNF ; 4KB8 ; 4KBA ; 4KBC ; 4KBK ; 4TN6 ; 4TW9 ; 4TWC ; 5IH4 ; 5IH5 ; 5IH6 ; 5MQV ; 5OKT ; 5W4W ; 6F1W ; 6F26 ; 6GZM ; 6HMP ; 6HMR ; 6PXN ; 6PXO ; 6PXP ; 6RCG ; 6RCH ; 6RU6 ; 6RU7 ; 6RU8 ; 7NZY ; 7P7F ; 7P7G ; 7P7H ; 7QR9 ; 7QRA ; 7QRB ; 8D7M ; 8D7N ; 8D7O ; 8D7P
• EC Number: 2.7.11.1; 2.7.11.26
• Pfam ID: PF00069
• Sequence:
  MELRVGNRYRLGRKIGSGSFGDIYLGTDIAAGEEVAIKLECVKTKHPQLHIESKIYKMMQ
  GGVGIPTIRWCGAEGDYNVMVMELLGPSLEDLFNFCSRKFSLKTVLLLADQMISRIEYIH
  SKNFIHRDVKPDNFLMGLGKKGNLVYIIDFGLAKKYRDARTHQHIPYRENKNLTGTARYA
  SINTHLGIEQSRRDDLESLGYVLMYFNLGSLPWQGLKAATKRQKYERISEKKMSTPIEVL
  CKGYPSEFATYLNFCRSLRFDDKPDYSYLRQLFRNLFHRQGFSYDYVFDWNMLKFGASRA
  ADDAERERRDREERLRHSRNPATRGLPSTASGRLRGTQEVAPPTPLTPTSHTANTSPRPV
  SGMERERKVSMRLHRGAPVNISSSDLTGRQDTSRMSTSQIPGRVASSGLQSVVHR
• Function: Essential serine/threonine-protein kinase that regulates diverse cellular growth and survival processes including Wnt signaling, DNA repair and circadian rhythms. It can phosphorylate a large number of proteins. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. Phosphorylates connexin-43/GJA1, MAP1A, SNAPIN, MAPT/TAU, TOP2A, DCK, HIF1A, EIF6, p53/TP53, DVL2, DVL3, ESR1, AIB1/NCOA3, DNMT1, PKD2, YAP1, PER1 and PER2. 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. YAP1 phosphorylation promotes its SCF(beta-TRCP) E3 ubiquitin ligase-mediated ubiquitination and subsequent degradation. DNMT1 phosphorylation reduces its DNA-binding activity. Phosphorylation of ESR1 and AIB1/NCOA3 stimulates their activity and coactivation. Phosphorylation of DVL2 and DVL3 regulates WNT3A signaling pathway that controls neurite outgrowth. Phosphorylates NEDD9/HEF1. EIF6 phosphorylation promotes its nuclear export. Triggers down-regulation of dopamine receptors in the forebrain. Activates DCK in vitro by phosphorylation. TOP2A phosphorylation favors DNA cleavable complex formation. May regulate the formation of the mitotic spindle apparatus in extravillous trophoblast. Modulates connexin-43/GJA1 gap junction assembly by phosphorylation. Probably involved in lymphocyte physiology. Regulates fast synaptic transmission mediated by glutamate.
• Tissue Specificity: Expressed in all tissues examined, including brain, heart, lung, liver, pancreas, kidney, placenta and skeletal muscle. However, kinase activity is not uniform, with highest kinase activity in splenocytes. In blood, highly expressed in hemopoietic cells and mature granulocytes. Also found in monocytes and lymphocytes.
• KEGG Pathway:
  Hedgehog sig.ling pathway (hsa04340)
  Hippo sig.ling pathway (hsa04390)
  Gap junction (hsa04540)
  Circadian rhythm (hsa04710)
• 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)
  COPII-mediated vesicle transport (R-HSA-204005)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced sleep phase syndrome	DIS28KRD	Supportive	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Casein kinase I isoform delta (CSNK1D).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Casein kinase I isoform delta (CSNK1D).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Casein kinase I isoform delta (CSNK1D).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Casein kinase I isoform delta (CSNK1D).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Casein kinase I isoform delta (CSNK1D).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Casein kinase I isoform delta (CSNK1D).	[16]

15 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 Casein kinase I isoform delta (CSNK1D).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Casein kinase I isoform delta (CSNK1D).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Casein kinase I isoform delta (CSNK1D).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Casein kinase I isoform delta (CSNK1D).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Casein kinase I isoform delta (CSNK1D).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Casein kinase I isoform delta (CSNK1D).	[9]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Casein kinase I isoform delta (CSNK1D).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Casein kinase I isoform delta (CSNK1D).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Casein kinase I isoform delta (CSNK1D).	[12]
R-roscovitine	DMSH108	Phase 2	R-roscovitine decreases the activity of Casein kinase I isoform delta (CSNK1D).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Casein kinase I isoform delta (CSNK1D).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Casein kinase I isoform delta (CSNK1D).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Casein kinase I isoform delta (CSNK1D).	[19]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Casein kinase I isoform delta (CSNK1D).	[20]
2,6-Dihydroanthra/1,9-Cd/Pyrazol-6-One	DMDN12L	Investigative	2,6-Dihydroanthra/1,9-Cd/Pyrazol-6-One decreases the activity of Casein kinase I isoform delta (CSNK1D).	[13]

References

• [1] Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome. Nature. 2005 Mar 31;434(7033):640-4. doi: 10.1038/nature03453.
• [2] 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.
• [3] 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.
• [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] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] 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.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] 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.
• [9] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [10] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] The specificities of protein kinase inhibitors: an update. Biochem J. 2003 Apr 1;371(Pt 1):199-204. doi: 10.1042/BJ20021535.
• [14] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.