Details of Drug Off-Target (DOT)

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

• DOT Name: Chloride intracellular channel protein 1 (CLIC1)
• Synonyms: Chloride channel ABP; Nuclear chloride ion channel 27; NCC27; Regulatory nuclear chloride ion channel protein; hRNCC
• Gene Name: CLIC1
• UniProt ID: CLIC1_HUMAN
• PDB ID: 1K0M; 1K0N; 1K0O; 1RK4; 3O3T; 3P8W; 3P90; 3QR6; 3SWL; 3TGZ; 3UVH; 4IQA; 4JZQ; 4K0G; 4K0N; 7F8R; 7FBQ
• Pfam ID: PF13410 ; PF13409
• Sequence:
  MAEEQPQVELFVKAGSDGAKIGNCPFSQRLFMVLWLKGVTFNVTTVDTKRRTETVQKLCP
  GGQLPFLLYGTEVHTDTNKIEEFLEAVLCPPRYPKLAALNPESNTAGLDIFAKFSAYIKN
  SNPALNDNLEKGLLKALKVLDNYLTSPLPEEVDETSAEDEGVSQRKFLDGNELTLADCNL
  LPKLHIVQVVCKKYRGFTIPEAFRGVHRYLSNAYAREEFASTCPDDEEIELAYEQVAKAL
  K
• Function: Can insert into membranes and form chloride ion channels. Channel activity depends on the pH. Membrane insertion seems to be redox-regulated and may occur only under oxydizing conditions. Involved in regulation of the cell cycle.
• Tissue Specificity: Expression is prominent in heart, placenta, liver, kidney and pancreas.

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Chloride intracellular channel protein 1 (CLIC1) affects the response to substance of Fluorouracil.	[24]
DTI-015	DMXZRW0	Approved	Chloride intracellular channel protein 1 (CLIC1) decreases the response to substance of DTI-015.	[25]

20 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Chloride intracellular channel protein 1 (CLIC1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Chloride intracellular channel protein 1 (CLIC1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Chloride intracellular channel protein 1 (CLIC1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Chloride intracellular channel protein 1 (CLIC1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Chloride intracellular channel protein 1 (CLIC1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Chloride intracellular channel protein 1 (CLIC1).	[6]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Chloride intracellular channel protein 1 (CLIC1).	[8]
Marinol	DM70IK5	Approved	Marinol increases the expression of Chloride intracellular channel protein 1 (CLIC1).	[9]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Chloride intracellular channel protein 1 (CLIC1).	[10]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Chloride intracellular channel protein 1 (CLIC1).	[11]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the expression of Chloride intracellular channel protein 1 (CLIC1).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Chloride intracellular channel protein 1 (CLIC1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Chloride intracellular channel protein 1 (CLIC1).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Chloride intracellular channel protein 1 (CLIC1).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Chloride intracellular channel protein 1 (CLIC1).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the expression of Chloride intracellular channel protein 1 (CLIC1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Chloride intracellular channel protein 1 (CLIC1).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Chloride intracellular channel protein 1 (CLIC1).	[8]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Chloride intracellular channel protein 1 (CLIC1).	[22]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Chloride intracellular channel protein 1 (CLIC1).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Chloride intracellular channel protein 1 (CLIC1).	[7]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Chloride intracellular channel protein 1 (CLIC1).	[21]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Dihydroartemisinin	DMBXVMZ	Approved	Dihydroartemisinin affects the binding of Chloride intracellular channel protein 1 (CLIC1).	[12]
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Chloride intracellular channel protein 1 (CLIC1).	[15]

References

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• [3] 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.
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• [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.
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• [9] Genomic and proteomic analysis of the effects of cannabinoids on normal human astrocytes. Brain Res. 2008 Jan 29;1191:1-11.
• [10] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [11] Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One. 2007 Nov 14;2(11):e1187. doi: 10.1371/journal.pone.0001187.
• [12] Untargeted Proteomics and Systems-Based Mechanistic Investigation of Artesunate in Human Bronchial Epithelial Cells. Chem Res Toxicol. 2015 Oct 19;28(10):1903-13. doi: 10.1021/acs.chemrestox.5b00105. Epub 2015 Sep 21.
• [13] ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res. 2012 Apr 1;18(7):1979-91. doi: 10.1158/1078-0432.CCR-11-2113. Epub 2012 Feb 20.
• [14] 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.
• [15] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [16] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [17] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [20] 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.
• [21] 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.
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• [24] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [25] Pharmacologic blockade of chloride channel synergistically enhances apoptosis of chemotherapeutic drug-resistant cancer stem cells. Biochem Biophys Res Commun. 2008 Sep 5;373(4):539-44. doi: 10.1016/j.bbrc.2008.06.070. Epub 2008 Jun 30.