Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9K0KI7)

• DOT Name: Claudin-15 (CLDN15)
• Gene Name: CLDN15
• Related Disease:
  Advanced cancer
  Common variable immunodeficiency
  Epithelioid mesothelioma
  Graft-versus-host disease
  Lung adenocarcinoma
  Malignant pleural mesothelioma
  Neoplasm
  Sickle-cell anaemia
• UniProt ID: CLD15_HUMAN
• Pfam ID: PF00822
• Sequence:
  MSMAVETFGFFMATVGLLMLGVTLPNSYWRVSTVHGNVITTNTIFENLWFSCATDSLGVY
  NCWEFPSMLALSGYIQACRALMITAILLGFLGLLLGIAGLRCTNIGGLELSRKAKLAATA
  GALHILAGICGMVAISWYAFNITRDFFDPLYPGTKYELGPALYLGWSASLISILGGLCLC
  SACCCGSDEDPAASARRPYQAPVSVMPVATSDQEGDSSFGKYGRNAYV
• Function: Claudins function as major constituents of the tight junction complexes that regulate the permeability of epithelia. While some claudin family members function as impermeable barriers, others mediate the permeability to ions and small molecules. Often, several claudin family members are coexpressed and interact with each other, and this determines the overall permeability. CLDN15 forms tight junctions that mediate the paracellular transport of small monovalent cations along a concentration gradient, due to selective permeability for Na(+), Li(+) and K(+) ions, but selects against Cl(-) ions. Plays an important role in paracellular Na(+) transport in the intestine and in Na(+) homeostasis. Required for normal Na(+)-dependent intestinal nutrient uptake.
• Tissue Specificity: Detected in colon (at protein level).
• 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

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[1]
Common variable immunodeficiency	DISHE7JQ	Limited	Altered Expression	[2]
Epithelioid mesothelioma	DIS17SNY	Limited	Altered Expression	[1]
Graft-versus-host disease	DIS0QADF	Limited	Altered Expression	[2]
Lung adenocarcinoma	DISD51WR	Limited	Altered Expression	[1]
Malignant pleural mesothelioma	DIST2R60	Limited	Altered Expression	[3]
Neoplasm	DISZKGEW	Limited	Altered Expression	[1]
Sickle-cell anaemia	DIS5YNZB	Limited	Altered Expression	[4]

3 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-15 (CLDN15).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Claudin-15 (CLDN15).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Claudin-15 (CLDN15).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Claudin-15 (CLDN15).	[6]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Claudin-15 (CLDN15).	[7]
Tetracycline	DMZA017	Approved	Tetracycline decreases the expression of Claudin-15 (CLDN15).	[8]
Rigosertib	DMOSTXF	Phase 3	Rigosertib affects the expression of Claudin-15 (CLDN15).	[9]

References

• [1] Claudin 3, 4, and 15 expression in solid tumors of lung adenocarcinoma versus malignant pleural mesothelioma.Ann Diagn Pathol. 2015 Aug;19(4):193-7. doi: 10.1016/j.anndiagpath.2015.03.007. Epub 2015 Apr 14.
• [2] Differential regulation of claudin-2 and claudin-15 expression in children and adults with malabsorptive disease.Lab Invest. 2020 Mar;100(3):483-490. doi: 10.1038/s41374-019-0324-8. Epub 2019 Oct 11.
• [3] Transcriptomic Analysis of the Claudin Interactome in Malignant Pleural Mesothelioma: Evaluation of the Effect of Disease Phenotype, Asbestos Exposure, and CDKN2A Deletion Status.Front Physiol. 2017 Mar 21;8:156. doi: 10.3389/fphys.2017.00156. eCollection 2017.
• [4] Depletion of Intestinal Microbiome Partially Rescues Bone Loss in Sickle Cell Disease Male Mice.Sci Rep. 2019 Jun 17;9(1):8659. doi: 10.1038/s41598-019-45270-4.
• [5] 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.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [7] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [8] Effects of residual levels of tetracycline on the barrier functions of human intestinal epithelial cells. Food Chem Toxicol. 2017 Nov;109(Pt 1):253-263. doi: 10.1016/j.fct.2017.09.004. Epub 2017 Sep 4.
• [9] 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.
• [10] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [11] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.