Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCXB7BI)

• DOT Name: Casein kinase I isoform gamma-1 (CSNK1G1)
• Synonyms: CKI-gamma 1; EC 2.7.11.1
• Gene Name: CSNK1G1
• Related Disease: Complex neurodevelopmental disorder
• UniProt ID: KC1G1_HUMAN
• PDB ID: 2CMW
• EC Number: 2.7.11.1
• Pfam ID: PF12605 ; PF00069
• Sequence:
  MDHPSREKDERQRTTKPMAQRSAHCSRPSGSSSSSGVLMVGPNFRVGKKIGCGNFGELRL
  GKNLYTNEYVAIKLEPIKSRAPQLHLEYRFYKQLGSAGEGLPQVYYFGPCGKYNAMVLEL
  LGPSLEDLFDLCDRTFTLKTVLMIAIQLLSRMEYVHSKNLIYRDVKPENFLIGRQGNKKE
  HVIHIIDFGLAKEYIDPETKKHIPYREHKSLTGTARYMSINTHLGKEQSRRDDLEALGHM
  FMYFLRGSLPWQGLKADTLKERYQKIGDTKRNTPIEALCENFPEEMATYLRYVRRLDFFE
  KPDYEYLRTLFTDLFEKKGYTFDYAYDWVGRPIPTPVGSVHVDSGASAITRESHTHRDRP
  SQQQPLRNQVVSSTNGELNVDDPTGAHSNAPITAHAEVEVVEEAKCCCFFKRKRKKTAQR
  HK
• Function: Serine/threonine-protein kinase. 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. Regulates fast synaptic transmission mediated by glutamate. Phosphorylates CLSPN.
• KEGG Pathway: Hedgehog sig.ling pathway (hsa04340)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal dominant	[1]

13 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 gamma-1 (CSNK1G1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Casein kinase I isoform gamma-1 (CSNK1G1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Casein kinase I isoform gamma-1 (CSNK1G1).	[4]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Casein kinase I isoform gamma-1 (CSNK1G1).	[5]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Casein kinase I isoform gamma-1 (CSNK1G1).	[6]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Casein kinase I isoform gamma-1 (CSNK1G1).	[7]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Casein kinase I isoform gamma-1 (CSNK1G1).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Casein kinase I isoform gamma-1 (CSNK1G1).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Casein kinase I isoform gamma-1 (CSNK1G1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Casein kinase I isoform gamma-1 (CSNK1G1).	[12]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Casein kinase I isoform gamma-1 (CSNK1G1).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Casein kinase I isoform gamma-1 (CSNK1G1).	[14]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Casein kinase I isoform gamma-1 (CSNK1G1).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Casein kinase I isoform gamma-1 (CSNK1G1).	[10]

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] 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] 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.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] 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.
• [6] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [7] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [8] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [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] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [14] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [15] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.