Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6KTPKD)

• DOT Name: Chloride intracellular channel protein 4 (CLIC4)
• Synonyms: Intracellular chloride ion channel protein p64H1
• Gene Name: CLIC4
• Related Disease:
  Adenocarcinoma
  Arteriosclerosis
  Atherosclerosis
  B-cell neoplasm
  Benign neoplasm
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Epithelial neoplasm
  Epithelial ovarian cancer
  Gastric cancer
  Glioma
  Hepatocellular carcinoma
  High blood pressure
  Myeloid leukaemia
  Neoplasm
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate neoplasm
  Pulmonary arterial hypertension
  Skin neoplasm
  Squamous cell carcinoma
  Stomach cancer
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Malignant pleural mesothelioma
  Osteoarthritis
  Pancreatic cancer
  Pancreatic ductal carcinoma
• UniProt ID: CLIC4_HUMAN
• PDB ID: 2AHE; 2D2Z; 3OQS
• Pfam ID: PF13409
• Sequence:
  MALSMPLNGLKEEDKEPLIELFVKAGSDGESIGNCPFSQRLFMILWLKGVVFSVTTVDLK
  RKPADLQNLAPGTHPPFITFNSEVKTDVNKIEEFLEEVLCPPKYLKLSPKHPESNTAGMD
  IFAKFSAYIKNSRPEANEALERGLLKTLQKLDEYLNSPLPDEIDENSMEDIKFSTRKFLD
  GNEMTLADCNLLPKLHIVKVVAKKYRNFDIPKEMTGIWRYLTNAYSRDEFTNTCPSDKEV
  EIAYSDVAKRLTK
• Function: Can insert into membranes and form poorly selective ion channels that may also transport chloride ions. Channel activity depends on the pH. Membrane insertion seems to be redox-regulated and may occur only under oxydizing conditions. Promotes cell-surface expression of HRH3. Has alternate cellular functions like a potential role in angiogenesis or in maintaining apical-basolateral membrane polarity during mitosis and cytokinesis. Could also promote endothelial cell proliferation and regulate endothelial morphogenesis (tubulogenesis).
• Tissue Specificity: Detected in epithelial cells from colon, esophagus and kidney (at protein level). Expression is prominent in heart, kidney, placenta and skeletal muscle.

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
B-cell neoplasm	DISVY326	Strong	Biomarker	[3]
Benign neoplasm	DISDUXAD	Strong	Biomarker	[4]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[6]
Epithelial neoplasm	DIS0T594	Strong	Biomarker	[7]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	Strong	Biomarker	[1]
Glioma	DIS5RPEH	Strong	Biomarker	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[9]
High blood pressure	DISY2OHH	Strong	Biomarker	[10]
Myeloid leukaemia	DISMN944	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[5]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[11]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[11]
Prostate cancer	DISF190Y	Strong	Biomarker	[12]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[12]
Pulmonary arterial hypertension	DISP8ZX5	Strong	Altered Expression	[10]
Skin neoplasm	DIS16DDV	Strong	Biomarker	[13]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[13]
Stomach cancer	DISKIJSX	Strong	Biomarker	[1]
Lung adenocarcinoma	DISD51WR	moderate	Genetic Variation	[14]
Lung cancer	DISCM4YA	moderate	Biomarker	[14]
Lung carcinoma	DISTR26C	moderate	Biomarker	[14]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[15]
Liver cancer	DISDE4BI	Limited	Biomarker	[15]
Malignant pleural mesothelioma	DIST2R60	Limited	Altered Expression	[16]
Osteoarthritis	DIS05URM	Limited	Biomarker	[17]
Pancreatic cancer	DISJC981	Limited	Altered Expression	[18]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Biomarker	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Chloride intracellular channel protein 4 (CLIC4).	[19]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Chloride intracellular channel protein 4 (CLIC4).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Chloride intracellular channel protein 4 (CLIC4).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Chloride intracellular channel protein 4 (CLIC4).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Chloride intracellular channel protein 4 (CLIC4).	[23]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Chloride intracellular channel protein 4 (CLIC4).	[24]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Chloride intracellular channel protein 4 (CLIC4).	[25]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Chloride intracellular channel protein 4 (CLIC4).	[27]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Chloride intracellular channel protein 4 (CLIC4).	[28]
Marinol	DM70IK5	Approved	Marinol increases the expression of Chloride intracellular channel protein 4 (CLIC4).	[29]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Chloride intracellular channel protein 4 (CLIC4).	[30]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Chloride intracellular channel protein 4 (CLIC4).	[31]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Chloride intracellular channel protein 4 (CLIC4).	[32]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Chloride intracellular channel protein 4 (CLIC4).	[33]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Chloride intracellular channel protein 4 (CLIC4).	[34]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Chloride intracellular channel protein 4 (CLIC4).	[35]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Chloride intracellular channel protein 4 (CLIC4).	[36]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Chloride intracellular channel protein 4 (CLIC4).	[37]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Chloride intracellular channel protein 4 (CLIC4).	[38]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Chloride intracellular channel protein 4 (CLIC4).	[39]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Chloride intracellular channel protein 4 (CLIC4).	[40]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Chloride intracellular channel protein 4 (CLIC4).	[41]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Chloride intracellular channel protein 4 (CLIC4).	[38]
CH-223191	DMMJZYC	Investigative	CH-223191 increases the expression of Chloride intracellular channel protein 4 (CLIC4).	[42]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl increases the expression of Chloride intracellular channel protein 4 (CLIC4).	[38]
Methyl Mercury Ion	DM6YEW4	Investigative	Methyl Mercury Ion increases the expression of Chloride intracellular channel protein 4 (CLIC4).	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the ubiquitination of Chloride intracellular channel protein 4 (CLIC4).	[26]

References

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• [2] MicroRNA-217-5p ameliorates endothelial cell apoptosis induced by ox-LDL by targeting CLIC4.Nutr Metab Cardiovasc Dis. 2020 Mar 9;30(3):523-533. doi: 10.1016/j.numecd.2019.09.027. Epub 2019 Oct 1.
• [3] The Combination of Arginine Deprivation and 5-Fluorouracil Improves Therapeutic Efficacy in Argininosuccinate Synthetase Negative Hepatocellular Carcinoma.Int J Mol Sci. 2017 Jun 1;18(6):1175. doi: 10.3390/ijms18061175.
• [4] CLIC1 and CLIC4 complement CA125 as a diagnostic biomarker panel for all subtypes of epithelial ovarian cancer.Sci Rep. 2018 Oct 3;8(1):14725. doi: 10.1038/s41598-018-32885-2.
• [5] Antisense suppression of the chloride intracellular channel family induces apoptosis, enhances tumor necrosis factor {alpha}-induced apoptosis, and inhibits tumor growth.Cancer Res. 2005 Jan 15;65(2):562-71.
• [6] Reciprocal modifications of CLIC4 in tumor epithelium and stroma mark malignant progression of multiple human cancers.Clin Cancer Res. 2007 Jan 1;13(1):121-31. doi: 10.1158/1078-0432.CCR-06-1562.
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• [11] Blockage of transdifferentiation from fibroblast to myofibroblast in experimental ovarian cancer models.Mol Cancer. 2009 Sep 27;8:78. doi: 10.1186/1476-4598-8-78.
• [12] Global analysis of differentially expressed genes in androgen-independent prostate cancer.Prostate Cancer Prostatic Dis. 2007;10(2):167-74. doi: 10.1038/sj.pcan.4500933. Epub 2007 Jan 2.
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• [17] Mitochondrial dysregulation of osteoarthritic human articular chondrocytes analyzed by proteomics: a decrease in mitochondrial superoxide dismutase points to a redox imbalance.Mol Cell Proteomics. 2009 Jan;8(1):172-89. doi: 10.1074/mcp.M800292-MCP200. Epub 2008 Sep 9.
• [18] Association of chloride intracellular channel 4 and Indian hedgehog proteins with survival of patients with pancreatic ductal adenocarcinoma.Int J Exp Pathol. 2016 Dec;97(6):422-429. doi: 10.1111/iep.12213. Epub 2017 Feb 16.
• [19] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
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• [21] 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.
• [22] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
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• [25] 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.
• [26] Quantitative Assessment of Arsenite-Induced Perturbation of Ubiquitinated Proteome. Chem Res Toxicol. 2022 Sep 19;35(9):1589-1597. doi: 10.1021/acs.chemrestox.2c00197. Epub 2022 Aug 22.
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• [28] Proteomic analysis revealed association of aberrant ROS signaling with suberoylanilide hydroxamic acid-induced autophagy in Jurkat T-leukemia cells. Autophagy. 2010 Aug;6(6):711-24. doi: 10.4161/auto.6.6.12397. Epub 2010 Aug 17.
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• [30] 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.
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• [32] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [33] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [34] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [35] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [36] 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.
• [37] MIP-1beta, a novel biomarker for in vitro sensitization test using human monocytic cell line. Toxicol In Vitro. 2006 Aug;20(5):736-42.
• [38] Inhibition of CXCL12-mediated chemotaxis of Jurkat cells by direct immunotoxicants. Arch Toxicol. 2016 Jul;90(7):1685-94. doi: 10.1007/s00204-015-1585-7. Epub 2015 Aug 28.
• [39] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [40] 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.
• [41] 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.
• [42] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.