Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT1ZAVI)

• DTT Name: Prostaglandin E2 receptor EP2 (PTGER2)
• Synonyms: Prostanoid EP2 receptor; Prostaglandin E2 receptor EP2 subtype; PGE2 receptor EP2 subtype; PGE receptor, EP2 subtype; PGE receptor EP2 subtype; EP2 receptor
• Gene Name: PTGER2
• DTT Type: Successful target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: PE2R2_HUMAN
• TTD ID: T38529
• Sequence:
  MGNASNDSQSEDCETRQWLPPGESPAISSVMFSAGVLGNLIALALLARRWRGDVGCSAGR
  RSSLSLFHVLVTELVFTDLLGTCLISPVVLASYARNQTLVALAPESRACTYFAFAMTFFS
  LATMLMLFAMALERYLSIGHPYFYQRRVSRSGGLAVLPVIYAVSLLFCSLPLLDYGQYVQ
  YCPGTWCFIRHGRTAYLQLYATLLLLLIVSVLACNFSVILNLIRMHRRSRRSRCGPSLGS
  GRGGPGARRRGERVSMAEETDHLILLAIMTITFAVCSLPFTIFAYMNETSSRKEKWDLQA
  LRFLSINSIIDPWVFAILRPPVLRLMRSVLCCRISLRTQDATQTSCSTQSDASKQADL
• Function: 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. Receptor for prostaglandin E2 (PGE2).
• KEGG Pathway:
  cAMP signaling pathway (hsa04024)
  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

6 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Alprostadil	DMWH7NQ	Aorta coarctation		Approved	[2]
Dinoprostone	DMTYOPD	Medical abortion	JA00.1Z	Approved	[3]
Iloprost	DMVPZBE	Pulmonary arterial hypertension	BB01.0	Approved	[1]
Mycophenolate mofetil	DMPQAGE	Hepatosplenic T-cell lymphoma		Approved	[4]
Omidenepag isopropyl	DMUX7Z8	Glaucoma/ocular hypertension	9C61	Approved	[5]
LAROPIPRANT	DM5FABJ	Coronary heart disease	BA80.Z	Phase 4	[6]

6 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	[7]
CP-533536	DMZEJLB	Osteoporosis	FB83.0	Phase 2	[8]
Taprenepag	DM1TSHL	Glaucoma/ocular hypertension	9C61	Phase 2	[9]
PF-4418948	DMMETU8	Endometriosis	GA10	Phase 1	[3]
TPST-1495	DM3GSB2	Solid tumour/cancer	2A00-2F9Z	Phase 1	[10]
PGF2alpha	DM4XAU7	Solid tumour/cancer	2A00-2F9Z	Clinical trial	[11]

16 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BUTAPROST	DMVYNJZ	Discovery agent	N.A.	Patented	[3]
PMID25772215-Compound-EP20082149552C9	DMVWF6I	N. A.	N. A.	Patented	[3]
PMID25772215-Compound-EP2149552diaminopyrimidines	DM48YKE	N. A.	N. A.	Patented	[3]
PMID25772215-Compound-US02014179750M1	DM7EKZ6	N. A.	N. A.	Patented	[3]
PMID25772215-Compound-US02014179750M2	DMC50F3	N. A.	N. A.	Patented	[3]
PMID25772215-Compound-US02014179750M3	DMJA1XC	N. A.	N. A.	Patented	[3]
PMID25772215-Compound-US02014179750TG6-10-1	DMWD1FP	N. A.	N. A.	Patented	[3]
PMID25772215-Compound-US02014179750TG6-129	DMRLZD2	N. A.	N. A.	Patented	[3]
PMID25772215-Compound-US02014179750TG7-112-2	DMB87WZ	N. A.	N. A.	Patented	[3]
PMID25772215-Compound-US02014179750TG7-170	DMORK8H	N. A.	N. A.	Patented	[3]
PMID25772215-Compound-US02014179750TG7-74	DM9I4EV	N. A.	N. A.	Patented	[3]
PMID25772215-Compound-US02014179750TG7-76	DMRTZC4	N. A.	N. A.	Patented	[3]
PMID25772215-Compound-US02014179750TG8-15	DM8IL6Y	N. A.	N. A.	Patented	[3]
PMID25772215-Compound-WO2012177618M4	DMD3CB4	N. A.	N. A.	Patented	[3]
PMID25772215-Compound-WO2012177618M5	DMWUK9X	N. A.	N. A.	Patented	[3]
PMID25772215-Compound-WO2012177618M6	DMDCZVI	N. A.	N. A.	Patented	[3]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ONO-8815Ly	DM4CVEG	Miscarriage	JA00.0	Terminated	[12]

23 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	[7]
17-phenyl-omega-trinor-PGE2	DM9OMI3	Discovery agent	N.A.	Investigative	[13]
19(R)-OH-PGE2	DMGUKCF	Discovery agent	N.A.	Investigative	[13]
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]
AH13205	DM2VEHG	Discovery agent	N.A.	Investigative	[7]
AH6809	DMKN3R9	Discovery agent	N.A.	Investigative	[15]
butaprost (free acid form)	DM5MZHP	Discovery agent	N.A.	Investigative	[11]
carbacyclin	DMMBQYE	Discovery agent	N.A.	Investigative	[15]
cicaprost	DM7ZJ4H	Discovery agent	N.A.	Investigative	[7]
isocarbacyclin	DMZR7W6	Discovery agent	N.A.	Investigative	[7]
M&B 28767	DMJQG82	Discovery agent	N.A.	Investigative	[13]
ONO-AE-248	DMA7VP5	Discovery agent	N.A.	Investigative	[16]
ONO-AE1-329	DMS3MZG	Discovery agent	N.A.	Investigative	[16]
PF-00212062	DMRHIMC	Solid tumour/cancer	2A00-2F9Z	Investigative	[4]
PGD2	DMYDW6J	Discovery agent	N.A.	Investigative	[11]
PMID20080612C1	DMV8ZFA	Discovery agent	N.A.	Investigative	[17]
R-65	DMSHMIK	Glaucoma/ocular hypertension	9C61	Investigative	[4]
TG4-155	DM862TI	Discovery agent	N.A.	Investigative	[18]
TG7-171	DM0OHL3	Discovery agent	N.A.	Investigative	[19]
U46619	DM13FX4	Discovery agent	N.A.	Investigative	[13]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Endometriosis	GA10	Endometrium tissue	2.77E-06	1.15	1.37
Osteoporosis	FA20	Bone marrow	1.73E-01	-1.29	-1.07

References

• [1] Exploration of prostanoid receptor subtype regulating estradiol and prostaglandin E2 induction of spinophilin in developing preoptic area neurons. Neuroscience. 2007 May 25;146(3):1117-27.
• [2] Emerging drugs for diabetic foot ulcers. Expert Opin Emerg Drugs. 2006 Nov;11(4):709-24.
• [3] 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.
• [4] 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: 341).
• [5] Clinical pipeline report, company report or official report of Santen Pharmaceutical.
• [6] Discovery of a potent and selective prostaglandin D2 receptor antagonist, [(3R)-4-(4-chloro-benzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydroc... J Med Chem. 2007 Feb 22;50(4):794-806.
• [7] 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.
• [8] Pfizer. Product Development Pipeline. March 31 2009.
• [9] A phase 2, randomized, dose-response trial of taprenepag isopropyl (PF-04217329) versus latanoprost 0.005% in open-angle glaucoma and ocular hypertension. Curr Eye Res. 2011 Sep;36(9):809-17.
• [10] Clinical pipeline report, company report or official report of Tempest Therapeutics.
• [11] Importance of the extracellular domain for prostaglandin EP(2) receptor function. Mol Pharmacol. 1999 Sep;56(3):545-51.
• [12] Prostaglandin E2 receptor type 2-selective agonist prevents the degeneration of articular cartilage in rabbit knees with traumatic instability. Arthritis Res Ther. 2011;13(5):R146.
• [13] Molecular cloning and characterization of the four rat prostaglandin E2 prostanoid receptor subtypes. Eur J Pharmacol. 1997 Dec 11;340(2-3):227-41.
• [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] 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.
• [16] 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.
• [17] Neuroprotection by selective allosteric potentiators of the EP2 prostaglandin receptor. Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2307-12.
• [18] Small molecule antagonist reveals seizure-induced mediation of neuronal injury by prostaglandin E2 receptor subtype EP2. Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):3149-54.
• [19] Development of second generation EP2 antagonists with high selectivity. Eur J Med Chem. 2014 Jul 23;82:521-35.