Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3ANRX1)

• DOT Name: Tumor necrosis factor ligand superfamily member 18 (TNFSF18)
• Synonyms: Activation-inducible TNF-related ligand; AITRL; Glucocorticoid-induced TNF-related ligand; hGITRL
• Gene Name: TNFSF18
• Related Disease:
  Atopic dermatitis
  Breast adenocarcinoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Lung neoplasm
  Acute myelogenous leukaemia
  Hashimoto thyroiditis
  Small lymphocytic lymphoma
  Mesothelioma
  Neoplasm
• UniProt ID: TNF18_HUMAN
• PDB ID: 2Q1M; 2R30; 2R32; 3B93; 3B94; 7KHD; 7LAW
• Sequence:
  MCLSHLENMPLSHSRTQGAQRSSWKLWLFCSIVMLLFLCSFSWLIFIFLQLETAKEPCMA
  KFGPLPSKWQMASSEPPCVNKVSDWKLEILQNGLYLIYGQVAPNANYNDVAPFEVRLYKN
  KDMIQTLTNKSKIQNVGGTYELHVGDTIDLIFNSEHQVLKNNTYWGIILLANPQFIS
• Function: Cytokine that binds to TNFRSF18/AITR/GITR. Regulates T-cell responses. Can function as costimulator and lower the threshold for T-cell activation and T-cell proliferation. Important for interactions between activated T-lymphocytes and endothelial cells. Mediates activation of NF-kappa-B. Triggers increased phosphorylation of STAT1 and up-regulates expression of VCAM1 and ICAM1. Promotes leukocyte adhesion to endothelial cells. Regulates migration of monocytes from the splenic reservoir to sites of inflammation.
• Tissue Specificity: Expressed at high levels in the small intestine, ovary, testis, kidney and endothelial cells.
• KEGG Pathway: Cytokine-cytokine receptor interaction (hsa04060)
• Reactome Pathway: TNFs bind their physiological receptors (R-HSA-5669034)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atopic dermatitis	DISTCP41	Strong	Biomarker	[1]
Breast adenocarcinoma	DISMPHJ0	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Lung neoplasm	DISVARNB	Strong	Biomarker	[4]
Acute myelogenous leukaemia	DISCSPTN	moderate	Altered Expression	[5]
Hashimoto thyroiditis	DIS77CDF	moderate	Biomarker	[6]
Small lymphocytic lymphoma	DIS30POX	moderate	Altered Expression	[5]
Mesothelioma	DISKWK9M	Disputed	Biomarker	[7]
Neoplasm	DISZKGEW	Disputed	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Tumor necrosis factor ligand superfamily member 18 (TNFSF18).	[8]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Tumor necrosis factor ligand superfamily member 18 (TNFSF18).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tumor necrosis factor ligand superfamily member 18 (TNFSF18).	[10]
PF-3758309	DM36PKZ	Phase 1	PF-3758309 decreases the expression of Tumor necrosis factor ligand superfamily member 18 (TNFSF18).	[11]

References

• [1] Glucocorticoid-induced tumour necrosis factor receptor (GITR) and its ligand (GITRL) in atopic dermatitis.Acta Derm Venereol. 2006;86(5):393-8. doi: 10.2340/00015555-0118.
• [2] Efficacy of cytokine-induced killer cells targeting CD40 and GITR.Oncol Lett. 2019 Feb;17(2):2425-2430. doi: 10.3892/ol.2018.9849. Epub 2018 Dec 18.
• [3] Expression of AITR and AITR ligand in breast cancer patients.Oncol Rep. 2007 Nov;18(5):1189-94.
• [4] IL15-Based Trifunctional Antibody-Fusion Proteins with Costimulatory TNF-Superfamily Ligands in the Single-Chain Format for Cancer Immunotherapy.Mol Cancer Ther. 2019 Jul;18(7):1278-1288. doi: 10.1158/1535-7163.MCT-18-1204. Epub 2019 Apr 30.
• [5] Generation and preclinical characterization of a Fc-optimized GITR-Ig fusion protein for induction of NK cell reactivity against leukemia.Mol Ther. 2013 Apr;21(4):877-86. doi: 10.1038/mt.2013.11. Epub 2013 Feb 5.
• [6] Th17/Treg cells imbalance and GITRL profile in patients with Hashimoto's thyroiditis.Int J Mol Sci. 2014 Nov 25;15(12):21674-86. doi: 10.3390/ijms151221674.
• [7] Progress of malignant mesothelioma research in basic science: A review of the 14th international conference of the international mesothelioma interest group (iMig2018).Lung Cancer. 2019 Jan;127:138-145. doi: 10.1016/j.lungcan.2018.11.034. Epub 2018 Nov 29.
• [8] Arsenic trioxide induces different gene expression profiles of genes related to growth and apoptosis in glioma cells dependent on the p53 status. Mol Biol Rep. 2008 Sep;35(3):421-9.
• [9] 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.
• [10] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [11] Inhibition of neuroblastoma proliferation by PF-3758309, a small-molecule inhibitor that targets p21-activated kinase 4. Oncol Rep. 2017 Nov;38(5):2705-2716. doi: 10.3892/or.2017.5989. Epub 2017 Sep 22.