Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTPNGDE)

• DTT Name: Prostaglandin E2 receptor EP3 (PTGER3)
• Synonyms: Prostanoid EP3 receptor; Prostaglandin E2 receptor EP3 subtype; PGE2-R; PGE2 receptor EP3 subtype; PGE receptor, EP3 subtype; PGE receptor EP3 subtype
• Gene Name: PTGER3
• DTT Type: Clinical trial target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: PE2R3_HUMAN
• TTD ID: T85467
• Sequence:
  MKETRGYGGDAPFCTRLNHSYTGMWAPERSAEARGNLTRPPGSGEDCGSVSVAFPITMLL
  TGFVGNALAMLLVSRSYRRRESKRKKSFLLCIGWLALTDLVGQLLTTPVVIVVYLSKQRW
  EHIDPSGRLCTFFGLTMTVFGLSSLFIASAMAVERALAIRAPHWYASHMKTRATRAVLLG
  VWLAVLAFALLPVLGVGQYTVQWPGTWCFISTGRGGNGTSSSHNWGNLFFASAFAFLGLL
  ALTVTFSCNLATIKALVSRCRAKATASQSSAQWGRITTETAIQLMGIMCVLSVCWSPLLI
  MMLKMIFNQTSVEHCKTHTEKQKECNFFLIAVRLASLNQILDPWVYLLLRKILLRKFCQI
  RYHTNNYASSSTSLPCQCSSTLMWSDHLER
• Function: The activity of this receptor can couple to both the inhibition of adenylate cyclase mediated by G(i) proteins, and to an elevation of intracellular calcium. Required for normal development of fever in response to pyrinogens, including IL1B, prostaglandin E2 and bacterial lipopolysaccharide (LPS). Required for normal potentiation of platelet aggregation by prostaglandin E2, and thus plays a role in the regulation of blood coagulation. Required for increased HCO3(-) secretion in the duodenum in response to mucosal acidification, and thereby contributes to the protection of the mucosa against acid-induced ulceration. Not required for normal kidney function, normal urine volume and osmolality. Receptor for prostaglandin E2 (PGE2).
• KEGG Pathway:
  Calcium signaling pathway (hsa04020)
  cAMP signaling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Regulation of lipolysis in adipocytes (hsa04923)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Prostanoid ligand receptors (R-HSA-391908)

Molecular Interaction Atlas (MIA) of This DTT

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
16,16-dimethyl-PGE2	DMNF38S	Stem cell engraftment	QB63.8	Phase 2	[2]
ONO-9054	DM5O6GC	Glaucoma/ocular hypertension	9C61	Phase 2	[3]
PGF2alpha	DM4XAU7	Solid tumour/cancer	2A00-2F9Z	Clinical trial	[2]

1 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BUTAPROST	DMVYNJZ	Discovery agent	N.A.	Patented	[1]

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
DG041	DMVO9WM	Peripheral vascular disease	BD4Z	Discontinued in Phase 2	[4]
GR-63799X	DM13GK8	Asthma	CA23	Discontinued in Phase 1	[5]

31 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
11-deoxy-PGE1	DM1ERJC	Discovery agent	N.A.	Investigative	[6]
17-phenyl-omega-trinor-PGE2	DM9OMI3	Discovery agent	N.A.	Investigative	[2]
3-(2-((E)-3-phenylprop-1-enyl)phenyl)acrylic acid	DM8P26J	Discovery agent	N.A.	Investigative	[7]
3-(2-(4-methoxycinnamyl)phenyl)acrylic acid	DM61CHU	Discovery agent	N.A.	Investigative	[7]
3-(2-(naphthalen-2-ylmethyl)phenyl)acrylic acid	DM9O5CH	Discovery agent	N.A.	Investigative	[7]
3-(2-cinnamylphenyl)acrylic acid	DM4XWME	Discovery agent	N.A.	Investigative	[7]
AH6809	DMKN3R9	Discovery agent	N.A.	Investigative	[8]
butaprost (free acid form)	DM5MZHP	Discovery agent	N.A.	Investigative	[8]
carbacyclin	DMMBQYE	Discovery agent	N.A.	Investigative	[2]
cicaprost	DM7ZJ4H	Discovery agent	N.A.	Investigative	[2]
cloprostenol	DMH01JV	Discovery agent	N.A.	Investigative	[8]
fluprostenol	DM9Q2PG	Discovery agent	N.A.	Investigative	[8]
FR-181157	DM2V7U1	Discovery agent	N.A.	Investigative	[9]
I-BOP	DMJAPML	Discovery agent	N.A.	Investigative	[2]
isocarbacyclin	DMZR7W6	Discovery agent	N.A.	Investigative	[2]
L-798,106	DM4FMGJ	Discovery agent	N.A.	Investigative	[10]
L-826266	DMYJ6QZ	Discovery agent	N.A.	Investigative	[11]
M&B 28767	DMJQG82	Discovery agent	N.A.	Investigative	[2]
Molecule 21	DMA7T0N	Pain	MG30-MG3Z	Investigative	[12]
ONO-8713	DMD2G65	Discovery agent	N.A.	Investigative	[6]
ONO-AE-248	DMA7VP5	Discovery agent	N.A.	Investigative	[13]
ONO-AE1-329	DMS3MZG	Discovery agent	N.A.	Investigative	[14]
ONO-AE2-227	DM78DO6	Discovery agent	N.A.	Investigative	[15]
ONO-AE3-208	DMEY7T4	Discovery agent	N.A.	Investigative	[16]
ONO-AE3-240	DMN3OWP	Discovery agent	N.A.	Investigative	[17]
ONO-AE5-599	DMDA7M9	Discovery agent	N.A.	Investigative	[18]
ONO-AP-324	DMA1NL9	Discovery agent	N.A.	Investigative	[19]
PGD2	DMYDW6J	Discovery agent	N.A.	Investigative	[6]
SC46275	DM6AS0P	Discovery agent	N.A.	Investigative	[20]
STA2	DMIYJ2M	Discovery agent	N.A.	Investigative	[2]
U46619	DM13FX4	Discovery agent	N.A.	Investigative	[8]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Asthma	CA23	Nasal and bronchial airway	4.36E-01	7.51E-03	0.03

References

• [1] Evaluation of WO 2012/177618 A1 and US-2014/0179750 A1: novel small molecule antagonists of prostaglandin-E2 receptor EP2.Expert Opin Ther Pat. 2015 Jul;25(7):837-44.
• [2] Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. Br J Pharmacol. 1997 Sep;122(2):217-24.
• [3] IOP-Lowering Effect of ONO-9054, A Novel Dual Agonist of Prostanoid EP3 and FP Receptors, in Monkeys. Invest Ophthalmol Vis Sci. 2015 Apr;56(4):2547-52.
• [4] BAY x 1005 attenuates atherosclerosis in apoE/LDLR - double knockout mice. J Physiol Pharmacol. 2007 Sep;58(3):583-8.
• [5] Effects of the prostanoid EP3-receptor agonists M&B 28767 and GR 63799X on infarct size caused by regional myocardial ischaemia in the anaesthetized rat. Br J Pharmacol. 1999 Feb;126(4):849-58.
• [6] Molecular cloning and characterization of the four rat prostaglandin E2 prostanoid receptor subtypes. Eur J Pharmacol. 1997 Dec 11;340(2-3):227-41.
• [7] Comparison between two classes of selective EP(3) antagonists and their biological activities. Bioorg Med Chem Lett. 2006 Nov 1;16(21):5639-42.
• [8] The utilization of recombinant prostanoid receptors to determine the affinities and selectivities of prostaglandins and related analogs. Biochim Biophys Acta. 2000 Jan 17;1483(2):285-93.
• [9] Metabolism investigation leading to novel drug design: orally active prostacyclin mimetics. Part 4. Bioorg Med Chem Lett. 2005 Jul 1;15(13):3284-7.
• [10] Dual modulation of urinary bladder activity and urine flow by prostanoid EP3 receptors in the conscious rat. Br J Pharmacol. 2009 Sep;158(1):372-81.
• [11] Roles of affinity and lipophilicity in the slow kinetics of prostanoid receptor antagonists on isolated smooth muscle preparations. Br J Pharmacol. 2011 Feb;162(4):863-79.
• [12] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 342).
• [13] Selective activation of the prostanoid EP(3) receptor reduces myocardial infarct size in rodents. Arterioscler Thromb Vasc Biol. 1999 Sep;19(9):2141-7.
• [14] The role of prostaglandin E receptor subtypes (EP1, EP2, EP3, and EP4) in bone resorption: an analysis using specific agonists for the respective EPs. Endocrinology. 2000 Apr;141(4):1554-9.
• [15] Involvement of prostaglandin E receptor subtype EP(4) in colon carcinogenesis. Cancer Res. 2002 Jan 1;62(1):28-32.
• [16] The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut. J Clin Invest. 2002 Apr;109(7):883-93.
• [17] Host prostaglandin E(2)-EP3 signaling regulates tumor-associated angiogenesis and tumor growth. J Exp Med. 2003 Jan 20;197(2):221-32.
• [18] Involvement of prostaglandin E receptor EP3 subtype in duodenal bicarbonate secretion in rats. Life Sci. 2007 Jun 6;80(26):2446-53.
• [19] Characterization of a prostanoid EP3-receptor in guinea-pig aorta: partial agonist action of the non-prostanoid ONO-AP-324. Br J Pharmacol. 1998 Nov;125(6):1288-96.
• [20] Investigation of the pronounced synergism between prostaglandin E2 and other constrictor agents on rat femoral artery. Prostaglandins Leukot Essent Fatty Acids. 2006 Jun;74(6):401-15.