Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO55YZI)

• DOT Name: Claudin-12 (CLDN12)
• Gene Name: CLDN12
• Related Disease:
  Autism spectrum disorder
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Lung cancer
  Lung carcinoma
  Lung squamous cell carcinoma
  Neoplasm
  Osteosarcoma
  Schizophrenia
  Colorectal carcinoma
  Colorectal neoplasm
• UniProt ID: CLD12_HUMAN
• Sequence:
  MGCRDVHAATVLSFLCGIASVAGLFAGTLLPNWRKLRLITFNRNEKNLTVYTGLWVKCAR
  YDGSSDCLMYDTTWYSSVDQLDLRVLQFALPLSMLIAMGALLLCLIGMCNTAFRSSVPNI
  KLAKCLVNSAGCHLVAGLLFFLAGTVSLSPSIWVIFYNIHLNKKFEPVFSFDYAVYVTIA
  SAGGLFMTSLILFIWYCTCKSLPSPFWQPLYSHPPSMHTYSQPYSARSRLSAIEIDIPVV
  SHTT
• Function: Plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity.
• 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

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[1]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Lung cancer	DISCM4YA	Strong	Altered Expression	[4]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[4]
Lung squamous cell carcinoma	DISXPIBD	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[2]
Schizophrenia	DISSRV2N	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[6]
Colorectal neoplasm	DISR1UCN	Limited	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Claudin-12 (CLDN12).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Claudin-12 (CLDN12).	[19]

15 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 Claudin-12 (CLDN12).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Claudin-12 (CLDN12).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Claudin-12 (CLDN12).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Claudin-12 (CLDN12).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Claudin-12 (CLDN12).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Claudin-12 (CLDN12).	[13]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Claudin-12 (CLDN12).	[13]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Claudin-12 (CLDN12).	[14]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Claudin-12 (CLDN12).	[15]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Claudin-12 (CLDN12).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Claudin-12 (CLDN12).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Claudin-12 (CLDN12).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Claudin-12 (CLDN12).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Claudin-12 (CLDN12).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Claudin-12 (CLDN12).	[22]

References

• [1] Blood-brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders.Mol Autism. 2016 Nov 29;7:49. doi: 10.1186/s13229-016-0110-z. eCollection 2016.
• [2] The Cytoplasmic Expression Of CLDN12 Predicts An Unfavorable Prognosis And Promotes Proliferation And Migration Of Osteosarcoma.Cancer Manag Res. 2019 Nov 1;11:9339-9351. doi: 10.2147/CMAR.S229441. eCollection 2019.
• [3] Interleukin-18 enhances breast cancer cell migration via down-regulation of claudin-12 and induction of the p38 MAPK pathway.Biochem Biophys Res Commun. 2015 Apr 10;459(3):379-86. doi: 10.1016/j.bbrc.2015.02.108. Epub 2015 Feb 27.
• [4] MicroRNA-146-5p promotes proliferation, migration and invasion in lung cancer cells by targeting claudin-12.Cancer Biomark. 2019;25(1):89-99. doi: 10.3233/CBM-182374.
• [5] Increased expression of claudin-12 promotes the metastatic phenotype of human bronchial epithelial cells and is associated with poor prognosis in lung squamous cell carcinoma.Exp Ther Med. 2019 Jan;17(1):165-174. doi: 10.3892/etm.2018.6964. Epub 2018 Nov 13.
• [6] Differential expression of genes encoding tight junction proteins in colorectal cancer: frequent dysregulation of claudin-1, -8 and -12.Int J Colorectal Dis. 2007 Jun;22(6):651-9. doi: 10.1007/s00384-006-0197-3. Epub 2006 Oct 18.
• [7] 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.
• [8] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [9] 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.
• [10] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [14] 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.
• [15] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [16] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [17] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [18] 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.
• [19] 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.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.