Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT79WV3)

• DTT Name: Prostaglandin E2 receptor EP4 (PTGER4)
• Synonyms: Prostanoid EP4 receptor; Prostaglandin E2 receptor EP4 subtype; PTGER2; PGE2 receptor EP4 subtype; PGE receptor EP4 subtype
• Gene Name: PTGER4
• DTT Type: Clinical trial target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: PE2R4_HUMAN
• TTD ID: T18876
• Sequence:
  MSTPGVNSSASLSPDRLNSPVTIPAVMFIFGVVGNLVAIVVLCKSRKEQKETTFYTLVCG
  LAVTDLLGTLLVSPVTIATYMKGQWPGGQPLCEYSTFILLFFSLSGLSIICAMSVERYLA
  INHAYFYSHYVDKRLAGLTLFAVYASNVLFCALPNMGLGSSRLQYPDTWCFIDWTTNVTA
  HAAYSYMYAGFSSFLILATVLCNVLVCGALLRMHRQFMRRTSLGTEQHHAAAAASVASRG
  HPAASPALPRLSDFRRRRSFRRIAGAEIQMVILLIATSLVVLICSIPLVVRVFVNQLYQP
  SLEREVSKNPDLQAIRIASVNPILDPWIYILLRKTVLSKAIEKIKCLFCRIGGSRRERSG
  QHCSDSQRTSSAMSGHSRSFISRELKEISSTSQTLLPDLSLPDLSENGLGGRNLLPGVPG
  MGLAQEDTTSLRTLRISETSDSSQGQDSESVLLVDEAGGSGRAGPAPKGSSLQVTFPSET
  LNLSEKCI
• Function: Receptor for prostaglandin E2 (PGE2). The activity of this receptor is mediated by G(s) proteins that stimulate adenylate cyclase. Has a relaxing effect on smooth muscle. May play an important role in regulating renal hemodynamics, intestinal epithelial transport, adrenal aldosterone secretion, and uterine function.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Renin secretion (hsa04924)
  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 DTT

11 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]
BGC-20-1531	DMS2MQ5	Migraine	8A80	Phase 2	[3]
ONO-AE1-437	DMCUGI8	Asthma	CA23	Phase 2	[4]
RQ-00000007 (oral)	DMMYTRU	Pain	MG30-MG3Z	Phase 2	[5]
IK-007	DMBLFPN	Non-small-cell lung cancer	2C25	Phase 1/2	[6]
AN0025	DMGSYPY	Aggressive cancer	2A00-2F9Z	Phase 1	[7]
E7046	DMFVT43	Rectal adenocarcinoma	2B92	Phase 1	[8]
ONO-4232	DMO4SD2	Acute heart failure	BD10-BD13	Phase 1	[9]
ONO-4578	DME63VK	Solid tumour/cancer	2A00-2F9Z	Phase 1	[8]
TPST-1495	DM3GSB2	Solid tumour/cancer	2A00-2F9Z	Phase 1	[10]
PGF2alpha	DM4XAU7	Solid tumour/cancer	2A00-2F9Z	Clinical trial	[11]

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]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ONO-4819	DMSVQK2	Fracture	ND56	Discontinued in Phase 2	[12]

32 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1-OH-PGE1	DMYHMEK	Discovery agent	N.A.	Investigative	[2]
11-deoxy-PGE1	DM1ERJC	Discovery agent	N.A.	Investigative	[13]
11-deoxy-PGE2	DMXLWOK	Discovery agent	N.A.	Investigative	[11]
13,14-dihydro-PGE1	DMTEACQ	Discovery agent	N.A.	Investigative	[13]
19(R)-OH-PGE2	DMGUKCF	Discovery agent	N.A.	Investigative	[11]
3-(2-((E)-3-phenylprop-1-enyl)phenyl)acrylic acid	DM8P26J	Discovery agent	N.A.	Investigative	[14]
3-(2-(4-methoxycinnamyl)phenyl)acrylic acid	DM61CHU	Discovery agent	N.A.	Investigative	[14]
3-(2-(naphthalen-2-ylmethyl)phenyl)acrylic acid	DM9O5CH	Discovery agent	N.A.	Investigative	[14]
3-(2-cinnamylphenyl)acrylic acid	DM4XWME	Discovery agent	N.A.	Investigative	[14]
8-aza-11-deoxyprostaglandin E1	DMYBPGA	Discovery agent	N.A.	Investigative	[15]
AH23848	DM4S1Y6	Discovery agent	N.A.	Investigative	[11]
butaprost (free acid form)	DM5MZHP	Discovery agent	N.A.	Investigative	[11]
carbacyclin	DMMBQYE	Discovery agent	N.A.	Investigative	[2]
cicaprost	DM7ZJ4H	Discovery agent	N.A.	Investigative	[16]
CP734432	DM9LYJT	Discovery agent	N.A.	Investigative	[17]
CR-5790	DMY2P5C	Osteoarthritis	FA00-FA05	Investigative	[18]
ER819762	DMSG91J	Discovery agent	N.A.	Investigative	[19]
FR-181157	DM2V7U1	Discovery agent	N.A.	Investigative	[20]
GW 627368	DM78KYC	Discovery agent	N.A.	Investigative	[21]
KAG-308	DMN4EUB	Ulcerative colitis	DD71	Investigative	[18]
L902688	DMIORW9	Discovery agent	N.A.	Investigative	[18]
M&B 28767	DMJQG82	Discovery agent	N.A.	Investigative	[2]
MK-2894	DMP4Q0J	Inflammation	1A00-CA43.1	Investigative	[18]
ONO-AE1-329	DMS3MZG	Discovery agent	N.A.	Investigative	[22]
ONO-AE2-227	DM78DO6	Discovery agent	N.A.	Investigative	[23]
ONO-AE3-208	DMEY7T4	Discovery agent	N.A.	Investigative	[24]
ONO-AE3-240	DMN3OWP	Discovery agent	N.A.	Investigative	[25]
PF-04475270	DMMHQL4	Glaucoma/ocular hypertension	9C61	Investigative	[18]
PGD2	DMYDW6J	Discovery agent	N.A.	Investigative	[11]
RQ-00000008	DMP9V7U	Inflammation	1A00-CA43.1	Investigative	[18]
TCS 2510	DMOLJRH	Discovery agent	N.A.	Investigative	[18]
U46619	DM13FX4	Discovery agent	N.A.	Investigative	[11]

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	4.39E-03	-0.29	-0.55
Osteoarthritis	FA20	Synovial tissue	5.27E-01	-0.05	-0.1

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] BGC20-1531, a novel, potent and selective prostanoid EP4 receptor antagonist: a putative new treatment for migraine headache. Br J Pharmacol. 2009 January; 156(2): 316-327.
• [4] An EP4 receptor agonist prevents indomethacin-induced closure of rat ductus arteriosus in vivo. Pediatr Res. 2004 Oct;56(4):586-90.
• [5] Clinical pipeline report, company report or official report of Avarx.
• [6] Grapiprant: an EP4 prostaglandin receptor antagonist and novel therapy for pain and inflammation. Vet Med Sci. 2015 Dec 21;2(1):3-9.
• [7] AN0025, a novel antagonist of PGE2-receptor E-type 4 (EP4), in combination with total neoadjuvant treatment of advanced rectal cancer. Radiother Oncol. 2023 Aug;185:109669.
• [8] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [9] ONO-4232, an EP4-selective Agonist, Improves Left Ventricular Diastolic Dysfunction and Ameliorates Acute and Chronic Heart Failure in Animal Models. Circulation. 2012; 126: A15345.
• [10] Clinical pipeline report, company report or official report of Tempest Therapeutics.
• [11] Molecular cloning and characterization of the four rat prostaglandin E2 prostanoid receptor subtypes. Eur J Pharmacol. 1997 Dec 11;340(2-3):227-41.
• [12] Effect of a prostaglandin EP4 receptor agonist on early fixation of hydroxyapatite/titanium composite- and titanium-coated rough-surfaced implants ... J Biomed Mater Res A. 2010 Mar 1;92(3):1202-9.
• [13] Pharmacological characterization of [(3)H]-prostaglandin E(2) binding to the cloned human EP(4) prostanoid receptor. Br J Pharmacol. 2000 Aug;130(8):1919-26.
• [14] Comparison between two classes of selective EP(3) antagonists and their biological activities. Bioorg Med Chem Lett. 2006 Nov 1;16(21):5639-42.
• [15] Lactams as EP4 prostanoid receptor agonists. 3. Discovery of N-ethylbenzoic acid 2-pyrrolidinones as subtype selective agents. J Med Chem. 2004 Dec 2;47(25):6124-7.
• [16] 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.
• [17] Ocular pharmacokinetics and hypotensive activity of PF-04475270, an EP4 prostaglandin agonist in preclinical models. Exp Eye Res. 2009 Nov;89(5):608-17.
• [18] 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: 343).
• [19] A novel antagonist of the prostaglandin E(2) EP(4) receptor inhibits Th1 differentiation and Th17 expansion and is orally active in arthritis models. Br J Pharmacol. 2010 May;160(2):292-310.
• [20] Discovery of diphenyloxazole and Ndelta-Z-ornithine derivatives as highly potent and selective human prostaglandin EP(4) receptor antagonists. J Med Chem. 2005 May 5;48(9):3103-6.
• [21] Piglet saphenous vein contains multiple relaxatory prostanoid receptors: evidence for EP4, EP2, DP and IP receptor subtypes. Br J Pharmacol. 2005 Feb;144(3):405-15.
• [22] 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.
• [23] Involvement of prostaglandin E receptor subtype EP(4) in colon carcinogenesis. Cancer Res. 2002 Jan 1;62(1):28-32.
• [24] The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut. J Clin Invest. 2002 Apr;109(7):883-93.
• [25] Host prostaglandin E(2)-EP3 signaling regulates tumor-associated angiogenesis and tumor growth. J Exp Med. 2003 Jan 20;197(2):221-32.