Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1AUZAA)

• DOT Name: Prostaglandin E2 receptor EP2 subtype (PTGER2)
• Synonyms: PGE receptor EP2 subtype; PGE2 receptor EP2 subtype; Prostanoid EP2 receptor
• Gene Name: PTGER2
• Related Disease: Asthma, nasal polyps, and aspirin intolerance
• UniProt ID: PE2R2_HUMAN
• PDB ID: 7CX2; 7CX3; 7CX4
• Pfam ID: PF00001
• Sequence:
  MGNASNDSQSEDCETRQWLPPGESPAISSVMFSAGVLGNLIALALLARRWRGDVGCSAGR
  RSSLSLFHVLVTELVFTDLLGTCLISPVVLASYARNQTLVALAPESRACTYFAFAMTFFS
  LATMLMLFAMALERYLSIGHPYFYQRRVSRSGGLAVLPVIYAVSLLFCSLPLLDYGQYVQ
  YCPGTWCFIRHGRTAYLQLYATLLLLLIVSVLACNFSVILNLIRMHRRSRRSRCGPSLGS
  GRGGPGARRRGERVSMAEETDHLILLAIMTITFAVCSLPFTIFAYMNETSSRKEKWDLQA
  LRFLSINSIIDPWVFAILRPPVLRLMRSVLCCRISLRTQDATQTSCSTQSDASKQADL
• Function: Receptor for prostaglandin E2 (PGE2). The activity of this receptor is mediated by G(s) proteins that stimulate adenylate cyclase. The subsequent raise in intracellular cAMP is responsible for the relaxing effect of this receptor on smooth muscle.
• Tissue Specificity: Placenta and lung.
• KEGG Pathway:
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Efferocytosis (hsa04148)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Renin secretion (hsa04924)
  Human cytomegalovirus infection (hsa05163)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  Prostanoid ligand receptors (R-HSA-391908)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Asthma, nasal polyps, and aspirin intolerance	DISWO2C4	Limited	Autosomal dominant	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Prostaglandin E2 receptor EP2 subtype (PTGER2) affects the response to substance of Aspirin.	[14]
Terbinafine	DMI6HUW	Approved	Prostaglandin E2 receptor EP2 subtype (PTGER2) increases the response to substance of Terbinafine.	[15]

3 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 Prostaglandin E2 receptor EP2 subtype (PTGER2).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Prostaglandin E2 receptor EP2 subtype (PTGER2).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Prostaglandin E2 receptor EP2 subtype (PTGER2).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Prostaglandin E2 receptor EP2 subtype (PTGER2).	[3]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Prostaglandin E2 receptor EP2 subtype (PTGER2).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Prostaglandin E2 receptor EP2 subtype (PTGER2).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Prostaglandin E2 receptor EP2 subtype (PTGER2).	[6]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Prostaglandin E2 receptor EP2 subtype (PTGER2).	[7]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Prostaglandin E2 receptor EP2 subtype (PTGER2).	[8]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Prostaglandin E2 receptor EP2 subtype (PTGER2).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Prostaglandin E2 receptor EP2 subtype (PTGER2).	[11]
NS398	DMINUWH	Terminated	NS398 decreases the expression of Prostaglandin E2 receptor EP2 subtype (PTGER2).	[12]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [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] 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.
• [4] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [5] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [6] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [7] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [8] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [9] Indomethacin decreases EP2 prostanoid receptor expression in colon cancer cells. Biochem Biophys Res Commun. 2007 Aug 3;359(3):568-73. doi: 10.1016/j.bbrc.2007.05.145. Epub 2007 May 30.
• [10] 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.
• [11] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [12] CHOP transcription factor mediates IL-8 signaling in cystic fibrosis bronchial epithelial cells. Am J Respir Cell Mol Biol. 2008 Feb;38(2):176-84. doi: 10.1165/rcmb.2007-0197OC. Epub 2007 Aug 20.
• [13] 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.
• [14] Polymorphisms in the prostaglandin E2 receptor subtype 2 gene confer susceptibility to aspirin-intolerant asthma: a candidate gene approach. Hum Mol Genet. 2004 Dec 15;13(24):3203-17. doi: 10.1093/hmg/ddh332. Epub 2004 Oct 20.
• [15] Suppressive effects of antimycotics on tumor necrosis factor-alpha-induced CCL27, CCL2, and CCL5 production in human keratinocytes. Biochem Pharmacol. 2006 Aug 14;72(4):463-73. doi: 10.1016/j.bcp.2006.05.001. Epub 2006 Jun 19.