Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBMLB80)

• DOT Name: Caspase recruitment domain-containing protein 18 (CARD18)
• Synonyms: Caspase-1 inhibitor Iceberg
• Gene Name: CARD18
• Related Disease:
  Acute coronary syndrome
  Lichen planus
  Skin disease
  Non-small-cell lung cancer
  Squamous cell carcinoma
• UniProt ID: CAR18_HUMAN
• PDB ID: 1DGN
• Pfam ID: PF00619
• Sequence:
  MADQLLRKKRRIFIHSVGAGTINALLDCLLEDEVISQEDMNKVRDENDTVMDKARVLIDL
  VTGKGPKSCCKFIKHLCEEDPQLASKMGLH
• Function: Inhibits generation of IL-1-beta by interacting with caspase-1 and preventing its association with RIP2. Down-regulates the release of IL1B.
• Tissue Specificity: Primarily expressed in the heart and placenta.
• KEGG Pathway: NOD-like receptor sig.ling pathway (hsa04621)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute coronary syndrome	DIS7DYEW	Strong	Genetic Variation	[1]
Lichen planus	DISRPMMS	Strong	Altered Expression	[2]
Skin disease	DISDW8R6	Strong	Altered Expression	[2]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[3]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[3]

4 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 Caspase recruitment domain-containing protein 18 (CARD18).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Caspase recruitment domain-containing protein 18 (CARD18).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Caspase recruitment domain-containing protein 18 (CARD18).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Caspase recruitment domain-containing protein 18 (CARD18).	[10]

4 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 Caspase recruitment domain-containing protein 18 (CARD18).	[5]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Caspase recruitment domain-containing protein 18 (CARD18).	[7]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Caspase recruitment domain-containing protein 18 (CARD18).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of Caspase recruitment domain-containing protein 18 (CARD18).	[11]

References

• [1] NLRC4 Inflammasome Is an Important Regulator of Interleukin-18 Levels in Patients With Acute Coronary Syndromes: Genome-Wide Association Study in the PLATelet inhibition and patient Outcomes Trial (PLATO).Circ Cardiovasc Genet. 2015 Jun;8(3):498-506. doi: 10.1161/CIRCGENETICS.114.000724. Epub 2015 Mar 6.
• [2] The caspase-1 inhibitor CARD18 is specifically expressed during late differentiation of keratinocytes and its expression is lost in lichen planus.J Dermatol Sci. 2017 Aug;87(2):176-182. doi: 10.1016/j.jdermsci.2017.04.015. Epub 2017 May 1.
• [3] MS4A1 dysregulation in asbestos-related lung squamous cell carcinoma is due to CD20 stromal lymphocyte expression.PLoS One. 2012;7(4):e34943. doi: 10.1371/journal.pone.0034943. Epub 2012 Apr 13.
• [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] 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.
• [6] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] 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.
• [8] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [9] 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.
• [10] 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.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.