Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5KUZ3A)

• DOT Name: Chloride intracellular channel protein 3 (CLIC3)
• Gene Name: CLIC3
• Related Disease:
  Bladder cancer
  Neoplasm
  Urinary bladder cancer
  Urinary bladder neoplasm
  Eclampsia
  Fetal growth restriction
  Matthew-Wood syndrome
  Pancreatic cancer
  Pancreatic ductal carcinoma
  Breast cancer
  Breast carcinoma
  Malignant pleural mesothelioma
• UniProt ID: CLIC3_HUMAN
• PDB ID: 3FY7; 3KJY
• Pfam ID: PF13410 ; PF13409
• Sequence:
  MAETKLQLFVKASEDGESVGHCPSCQRLFMVLLLKGVPFTLTTVDTRRSPDVLKDFAPGS
  QLPILLYDSDAKTDTLQIEDFLEETLGPPDFPSLAPRYRESNTAGNDVFHKFSAFIKNPV
  PAQDEALYQQLLRALARLDSYLRAPLEHELAGEPQLRESRRRFLDGDRLTLADCSLLPKL
  HIVDTVCAHFRQAPIPAELRGVRRYLDSAMQEKEFKYTCPHSAEILAAYRPAVHPR
• Function: Can insert into membranes and form chloride ion channels. May participate in cellular growth control.
• Tissue Specificity: Detected in placenta (at protein level). Widely expressed. High expression is found in placenta followed by lung and heart. Low expression in skeletal muscle, kidney and pancreas.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder cancer	DISUHNM0	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Posttranslational Modification	[2]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[1]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[1]
Eclampsia	DISWPO8U	moderate	Biomarker	[3]
Fetal growth restriction	DIS5WEJ5	moderate	Biomarker	[3]
Matthew-Wood syndrome	DISA7HR7	moderate	Biomarker	[4]
Pancreatic cancer	DISJC981	moderate	Biomarker	[5]
Pancreatic ductal carcinoma	DIS26F9Q	moderate	Altered Expression	[4]
Breast cancer	DIS7DPX1	Limited	Biomarker	[6]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[6]
Malignant pleural mesothelioma	DIST2R60	Limited	Altered Expression	[7]

1 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 Chloride intracellular channel protein 3 (CLIC3).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Chloride intracellular channel protein 3 (CLIC3).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Chloride intracellular channel protein 3 (CLIC3).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Chloride intracellular channel protein 3 (CLIC3).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Chloride intracellular channel protein 3 (CLIC3).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Chloride intracellular channel protein 3 (CLIC3).	[13]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Chloride intracellular channel protein 3 (CLIC3).	[14]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Chloride intracellular channel protein 3 (CLIC3).	[15]
Ampicillin	DMHWE7P	Approved	Ampicillin increases the expression of Chloride intracellular channel protein 3 (CLIC3).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Chloride intracellular channel protein 3 (CLIC3).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Chloride intracellular channel protein 3 (CLIC3).	[18]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Chloride intracellular channel protein 3 (CLIC3).	[19]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Chloride intracellular channel protein 3 (CLIC3).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Chloride intracellular channel protein 3 (CLIC3).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Chloride intracellular channel protein 3 (CLIC3).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Chloride intracellular channel protein 3 (CLIC3).	[22]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Chloride intracellular channel protein 3 (CLIC3).	[23]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Chloride intracellular channel protein 3 (CLIC3).	[24]

References

• [1] CLT1 targets bladder cancer through integrin 51 and CLIC3.Mol Cancer Res. 2013 Feb;11(2):194-203. doi: 10.1158/1541-7786.MCR-12-0300. Epub 2012 Nov 30.
• [2] Epigenetic screening of salivary gland mucoepidermoid carcinoma identifies hypomethylation of CLIC3 as a common alteration.Oral Oncol. 2015 Dec;51(12):1120-5. doi: 10.1016/j.oraloncology.2015.09.010. Epub 2015 Oct 17.
• [3] Placental CLIC3 is increased in fetal growth restriction and pre-eclampsia affected human pregnancies.Placenta. 2012 Sep;33(9):741-4. doi: 10.1016/j.placenta.2012.06.011. Epub 2012 Jul 11.
• [4] Rab25 and CLIC3 collaborate to promote integrin recycling from late endosomes/lysosomes and drive cancer progression.Dev Cell. 2012 Jan 17;22(1):131-45. doi: 10.1016/j.devcel.2011.11.008. Epub 2011 Dec 22.
• [5] Intracellular Ion Channels in Pancreas Cancer.Cell Physiol Biochem. 2019;53(S1):44-51. doi: 10.33594/000000193.
• [6] CLIC3 controls recycling of late endosomal MT1-MMP and dictates invasion and metastasis in breast cancer.J Cell Sci. 2014 Sep 15;127(Pt 18):3893-901. doi: 10.1242/jcs.135947. Epub 2014 Jul 11.
• [7] Transcriptional over-expression of chloride intracellular channels 3 and 4 in malignant pleural mesothelioma.Comput Biol Chem. 2015 Dec;59 Pt A:111-6. doi: 10.1016/j.compbiolchem.2015.09.012. Epub 2015 Sep 28.
• [8] 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.
• [9] 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.
• [10] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [11] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Transforming growth factor beta1 targets estrogen receptor signaling in bronchial epithelial cells. Respir Res. 2018 Aug 30;19(1):160. doi: 10.1186/s12931-018-0861-5.
• [14] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [15] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [16] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.
• [19] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [20] Gene expression preferentially regulated by tamoxifen in breast cancer cells and correlations with clinical outcome. Cancer Res. 2006 Jul 15;66(14):7334-40.
• [21] 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.
• [22] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [23] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [24] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.