Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHO1BLK)

• DOT Name: Adenosine receptor A3 (ADORA3)
• Gene Name: ADORA3
• UniProt ID: AA3R_HUMAN
• Pfam ID: PF00001
• Sequence:
  MPNNSTALSLANVTYITMEIFIGLCAIVGNVLVICVVKLNPSLQTTTFYFIVSLALADIA
  VGVLVMPLAIVVSLGITIHFYSCLFMTCLLLIFTHASIMSLLAIAVDRYLRVKLTVRYKR
  VTTHRRIWLALGLCWLVSFLVGLTPMFGWNMKLTSEYHRNVTFLSCQFVSVMRMDYMVYF
  SFLTWIFIPLVVMCAIYLDIFYIIRNKLSLNLSNSKETGAFYGREFKTAKSLFLVLFLFA
  LSWLPLSIINCIIYFNGEVPQLVLYMGILLSHANSMMNPIVYAYKIKKFKETYLLILKAC
  VVCHPSDSLDTSIEKNSE
• Function: [Isoform 2]: Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibits adenylyl cyclase.
• Tissue Specificity: Expressed in the lung and bone. Expressed at lower levels in osteosarcoma tissues (at protein level).
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  Sphingolipid sig.ling pathway (hsa04071)
  Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Adenosine P1 receptors (R-HSA-417973)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Adenosine receptor A3 (ADORA3) affects the response to substance of Aspirin.	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Adenosine receptor A3 (ADORA3).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Adenosine receptor A3 (ADORA3).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Adenosine receptor A3 (ADORA3).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of Adenosine receptor A3 (ADORA3).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Adenosine receptor A3 (ADORA3).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Adenosine receptor A3 (ADORA3).	[4]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Adenosine receptor A3 (ADORA3).	[5]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Adenosine receptor A3 (ADORA3).	[6]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Adenosine receptor A3 (ADORA3).	[7]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Adenosine receptor A3 (ADORA3).	[8]
Adenosine	DMM2NSK	Approved	Adenosine increases the expression of Adenosine receptor A3 (ADORA3).	[9]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Adenosine receptor A3 (ADORA3).	[2]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Adenosine receptor A3 (ADORA3).	[10]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Adenosine receptor A3 (ADORA3).	[13]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
[3H]NECA	DMAO9SH	Investigative	[3H]NECA affects the binding of Adenosine receptor A3 (ADORA3).	[14]
MRE 3008F20	DM72US0	Investigative	MRE 3008F20 affects the binding of Adenosine receptor A3 (ADORA3).	[15]

References

• [1] 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.
• [2] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] 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.
• [5] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [6] Methotrexate enhances the anti-inflammatory effect of CF101 via up-regulation of the A3 adenosine receptor expression. Arthritis Res Ther. 2006;8(6):R169. doi: 10.1186/ar2078.
• [7] Indomethacin stimulates activity and expression of ecto-5'-nucleotidase/CD73 in glioma cell lines. Eur J Pharmacol. 2007 Aug 13;569(1-2):8-15.
• [8] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [9] Adenosine up-regulates vascular endothelial growth factor in human macrophages. Biochem Biophys Res Commun. 2010 Feb 12;392(3):351-6. doi: 10.1016/j.bbrc.2010.01.023. Epub 2010 Jan 11.
• [10] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [11] 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.
• [12] 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.
• [13] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [14] Pyrimidine derivatives as potent and selective A3 adenosine receptor antagonists. J Med Chem. 2011 Jan 27;54(2):457-71. doi: 10.1021/jm100843z. Epub 2010 Dec 27.
• [15] New 2-heterocyclyl-imidazo[2,1-i]purin-5-one derivatives as potent and selective human A3 adenosine receptor antagonists. J Med Chem. 2011 Jul 28;54(14):5205-20. doi: 10.1021/jm2004738. Epub 2011 Jun 28.
• [16] Functional variability of the adenosine A3 receptor (ADORA3) gene polymorphism in aspirin-induced urticaria. Br J Dermatol. 2010 Nov;163(5):977-85. doi: 10.1111/j.1365-2133.2010.09983.x.