Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCKI2IZ)

• DOT Name: Claudin-9 (CLDN9)
• Gene Name: CLDN9
• Related Disease:
  Hepatocellular carcinoma
  Prostate cancer
  Prostate neoplasm
  Sensorineural hearing loss disorder
  Hearing loss, autosomal recessive 116
• UniProt ID: CLD9_HUMAN
• PDB ID: 6OV2; 6OV3
• Pfam ID: PF00822
• Sequence:
  MASTGLELLGMTLAVLGWLGTLVSCALPLWKVTAFIGNSIVVAQVVWEGLWMSCVVQSTG
  QMQCKVYDSLLALPQDLQAARALCVIALLLALLGLLVAITGAQCTTCVEDEGAKARIVLT
  AGVILLLAGILVLIPVCWTAHAIIQDFYNPLVAEALKRELGASLYLGWAAAALLMLGGGL
  LCCTCPPPQVERPRGPRLGYSIPSRSGASGLDKRDYV
• Function: Plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity; (Microbial infection) Acts as a receptor for hepatitis C virus (HCV) entry into hepatic cells.
• Tissue Specificity: Expressed in the liver, in peripheral blood mononuclear cells and hepatocarcinoma cell lines.
• KEGG Pathway:
  Cell adhesion molecules (hsa04514)
  Tight junction (hsa04530)
  Leukocyte transendothelial migration (hsa04670)
  Pathogenic Escherichia coli infection (hsa05130)
  Hepatitis C (hsa05160)
• Reactome Pathway: Tight junction interactions (R-HSA-420029)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[1]
Prostate cancer	DISF190Y	Strong	Biomarker	[2]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[2]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Biomarker	[3]
Hearing loss, autosomal recessive 116	DIS2D26C	Limited	Unknown	[3]

2 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 Claudin-9 (CLDN9).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Claudin-9 (CLDN9).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Claudin-9 (CLDN9).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Claudin-9 (CLDN9).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Claudin-9 (CLDN9).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Claudin-9 (CLDN9).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Claudin-9 (CLDN9).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Claudin-9 (CLDN9).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Claudin-9 (CLDN9).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Claudin-9 (CLDN9).	[12]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Claudin-9 (CLDN9).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Claudin-9 (CLDN9).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Claudin-9 (CLDN9).	[10]

References

• [1] Claudin-9 enhances the metastatic potential of hepatocytes via Tyk2/Stat3 signaling.Turk J Gastroenterol. 2019 Aug;30(8):722-731. doi: 10.5152/tjg.2019.18513.
• [2] Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.Prostate. 2007 Jan 1;67(1):83-106. doi: 10.1002/pros.20505.
• [3] A truncating CLDN9 variant is associated with autosomal recessive nonsyndromic hearing loss. Hum Genet. 2019 Oct;138(10):1071-1075. doi: 10.1007/s00439-019-02037-1. Epub 2019 Jun 7.
• [4] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [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] Prevention of murine experimental corneal trauma by epigenetic events regulating claudin 6 and claudin 9. Jpn J Ophthalmol. 2008 May-Jun;52(3):195-203. doi: 10.1007/s10384-008-0524-z. Epub 2008 Jul 27.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [13] 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.
• [14] 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.