Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAD976B)

• DOT Name: ICOS ligand (ICOSLG)
• Synonyms: B7 homolog 2; B7-H2; B7-like protein Gl50; B7-related protein 1; B7RP-1; CD antigen CD275
• Gene Name: ICOSLG
• Related Disease: Combined immunodeficiency
• UniProt ID: ICOSL_HUMAN
• PDB ID: 6X4G; 6X4T
• Pfam ID: PF07686
• Sequence:
  MRLGSPGLLFLLFSSLRADTQEKEVRAMVGSDVELSCACPEGSRFDLNDVYVYWQTSESK
  TVVTYHIPQNSSLENVDSRYRNRALMSPAGMLRGDFSLRLFNVTPQDEQKFHCLVLSQSL
  GFQEVLSVEVTLHVAANFSVPVVSAPHSPSQDELTFTCTSINGYPRPNVYWINKTDNSLL
  DQALQNDTVFLNMRGLYDVVSVLRIARTPSVNIGCCIENVLLQQNLTVGSQTGNDIGERD
  KITENPVSTGEKNAATWSILAVLCLLVVVAVAIGWVCRDRCLQHSYAGAWAVSPETELTG
  HV
• Function: Ligand for the T-cell-specific cell surface receptor ICOS. Acts as a costimulatory signal for T-cell proliferation and cytokine secretion; induces also B-cell proliferation and differentiation into plasma cells. Could play an important role in mediating local tissue responses to inflammatory conditions, as well as in modulating the secondary immune response by co-stimulating memory T-cell function.
• Tissue Specificity: Isoform 1 is widely expressed (brain, heart, kidney, liver, lung, pancreas, placenta, skeletal muscle, bone marrow, colon, ovary, prostate, testis, lymph nodes, leukocytes, spleen, thymus and tonsil), while isoform 2 is detected only in lymph nodes, leukocytes and spleen. Expressed on activated monocytes and dendritic cells.
• KEGG Pathway:
  Cell adhesion molecules (hsa04514)
  Intesti.l immune network for IgA production (hsa04672)
• Reactome Pathway: Costimulation by the CD28 family (R-HSA-388841)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Combined immunodeficiency	DISKR6QJ	Moderate	Autosomal recessive	[1]

1 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 ICOS ligand (ICOSLG).	[2]

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 ICOS ligand (ICOSLG).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ICOS ligand (ICOSLG).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of ICOS ligand (ICOSLG).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of ICOS ligand (ICOSLG).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of ICOS ligand (ICOSLG).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of ICOS ligand (ICOSLG).	[8]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of ICOS ligand (ICOSLG).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of ICOS ligand (ICOSLG).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of ICOS ligand (ICOSLG).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of ICOS ligand (ICOSLG).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of ICOS ligand (ICOSLG).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of ICOS ligand (ICOSLG).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of ICOS ligand (ICOSLG).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of ICOS ligand (ICOSLG).	[16]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of ICOS ligand (ICOSLG).	[17]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] 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.
• [3] 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.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] 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.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.