Target Information

Target General Information

Target ID

T18876 (Former ID: TTDC00151)

Target Name

Prostaglandin E2 receptor EP4 (PTGER4)

Synonyms

Prostanoid EP4 receptor; Prostaglandin E2 receptor EP4 subtype; PTGER2; PGE2 receptor EP4 subtype; PGE receptor EP4 subtype

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Gene Name

PTGER4

Target Type

Clinical trial target

[1]

Disease

[+] 8 Target-related Diseases

Asthma [ICD-11: CA23]

Migraine [ICD-11: 8A80]

Pain [ICD-11: MG30-MG3Z]

Transplanted organ/tissue [ICD-11: QB63]

Non-small-cell lung cancer [ICD-11: 2C25]

Heart failure [ICD-11: BD10-BD1Z]

Rectum cancer [ICD-11: 2B92]

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

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.

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BioChemical Class

GPCR rhodopsin

UniProt ID

PE2R4_HUMAN

Sequence

MSTPGVNSSASLSPDRLNSPVTIPAVMFIFGVVGNLVAIVVLCKSRKEQKETTFYTLVCG
LAVTDLLGTLLVSPVTIATYMKGQWPGGQPLCEYSTFILLFFSLSGLSIICAMSVERYLA
INHAYFYSHYVDKRLAGLTLFAVYASNVLFCALPNMGLGSSRLQYPDTWCFIDWTTNVTA
HAAYSYMYAGFSSFLILATVLCNVLVCGALLRMHRQFMRRTSLGTEQHHAAAAASVASRG
HPAASPALPRLSDFRRRRSFRRIAGAEIQMVILLIATSLVVLICSIPLVVRVFVNQLYQP
SLEREVSKNPDLQAIRIASVNPILDPWIYILLRKTVLSKAIEKIKCLFCRIGGSRRERSG
QHCSDSQRTSSAMSGHSRSFISRELKEISSTSQTLLPDLSLPDLSENGLGGRNLLPGVPG
MGLAQEDTTSLRTLRISETSDSSQGQDSESVLLVDEAGGSGRAGPAPKGSSLQVTFPSET
LNLSEKCI

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3D Structure

Click to Show 3D Structure of This Target

AlphaFold

HIT2.0 ID

T68O49

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 7 Clinical Trial Drugs

BGC-20-1531

Drug Info

Phase 2

Migraine

[3], [4]

ONO-AE1-437

Drug Info

Phase 2

Asthma

[5]

RQ-00000007 (oral)

Drug Info

Phase 2

Pain

[6], [7]

E7046

Drug Info

Phase 1

Rectal adenocarcinoma

[11]

ONO-4232

Drug Info

Phase 1

Acute heart failure

[12]

ONO-4578

Drug Info

Phase 1

Solid tumour/cancer

[11]

PGF2alpha

Drug Info

Clinical trial

Solid tumour/cancer

[13]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

ONO-4819

Drug Info

Discontinued in Phase 2

Fracture

[14], [15]

Mode of Action

[+] 3 Modes of Action

Antagonist

[+] 13 Antagonist drugs

BGC-20-1531

Drug Info

[16]

RQ-00000007 (oral)

Drug Info

[18]

E7046

Drug Info

[11]

ONO-4578

Drug Info

[11]

AH23848

Drug Info

[20]

CR-5790

Drug Info

[29]

ER819762

Drug Info

[30]

GW 627368

Drug Info

[32]

MK-2894

Drug Info

[29]

ONO-AE2-227

Drug Info

[34]

ONO-AE3-208

Drug Info

[35]

ONO-AE3-240

Drug Info

[36]

RQ-00000008

Drug Info

[29]

Agonist

[+] 19 Agonist drugs

ONO-AE1-437

Drug Info

[17]

ONO-4232

Drug Info

[19]

PGF2alpha

Drug Info

[20]

ONO-4819

Drug Info

[21], [22], [23]

1-OH-PGE1

Drug Info

[24]

11-deoxy-PGE1

Drug Info

[25]

11-deoxy-PGE2

Drug Info

[20]

13,14-dihydro-PGE1

Drug Info

[25]

19(R)-OH-PGE2

Drug Info

[20]

butaprost (free acid form)

Drug Info

[20]

cicaprost

Drug Info

[28]

KAG-308

Drug Info

[29]

L902688

Drug Info

[29]

M&B 28767

Drug Info

[24]

ONO-AE1-329

Drug Info

[33]

PF-04475270

Drug Info

[29]

PGD2

Drug Info

[20]

TCS 2510

Drug Info

[29]

U46619

Drug Info

[20]

Inhibitor

[+] 4 Inhibitor drugs

3-(2-(4-methoxycinnamyl)phenyl)acrylic acid

Drug Info

[26]

3-(2-cinnamylphenyl)acrylic acid

Drug Info

[26]

8-aza-11-deoxyprostaglandin E1

Drug Info

[27]

FR-181157

Drug Info

[31]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: Dinoprostone

Ligand Info

Structure Description

Cryo-EM Structure of the Prostaglandin E Receptor EP4 Coupled to G Protein

PDB:7D7M

Method

Electron microscopy

Resolution

3.30 Å

Mutation

Yes

[37]

PDB Sequence

SPVTIPAVMF

²⁸

IFGVVGNLVA

³⁸

IVVLCKSRKE

⁴⁸

QKETTFYTLV

⁵⁸

CGLAVTDLLG

⁶⁸

TLLVSPVTIA

⁷⁸

TYMKGQWPGG

⁸⁸

QPLCEYSTFI

⁹⁸

LLFFSLSGLS

¹⁰⁸

IICAMSVERY

¹¹⁸

LAINHAYFYS

¹²⁸

HYVDKRLAGL

¹³⁸

TLFAVYASNV

¹⁴⁸

LFCALPNMGL

¹⁵⁸

GSSRLQYPDT

¹⁶⁸

WCFIDWTTQV

¹⁷⁸

TAHAAYSYMY

¹⁸⁸

AGFSSFLILA

¹⁹⁸

TVLCNVLVCG

²⁰⁸

ALLRMHRQFF

²⁶⁰

RRIAGAEIQM

²⁷⁰

VILLIATSLV

²⁸⁰

VLICSIPLVV

²⁹⁰

RVFVNQLYQP

³⁰⁰

SLEREVSKNP

³¹⁰

DLQAIRIASV

³²⁰

NPILDPWIYI

³³⁰

LLRKTVLSKA

³⁴⁰

IEKIK

Residue

Distance (Å)

PRO20

4.906

PRO24

3.447

MET27

3.120

PHE28

4.084

GLY68

3.771

THR69

3.080

VAL72

3.412

SER73

3.294

THR76

3.293

TYR80

3.133

LEU99

3.708

PHE102

4.799

Residue

Distance (Å)

SER103

3.526

PRO166

3.924

THR168

3.271

TRP169

3.823

LEU288

3.859

LEU312

3.371

ILE315

3.705

ARG316

3.338

ALA318

3.412

SER319

3.625

PRO322

4.245

ILE323

4.467

Ligand Name: 4-[4-cyano-2-[[(2R)-2-(4-fluoranylnaphthalen-1-yl)propanoyl]amino]phenyl]butanoic acid

Ligand Info

Structure Description

Crystal structure of the human prostaglandin E receptor EP4 in complex with Fab and ONO-AE3-208

PDB:5YWY

Method

X-ray diffraction

Resolution

3.20 Å

Mutation

Yes

[38]

PDB Sequence

NSPVTIPAVM

²⁷

FIFGVVGNLV

³⁷

AIVVLCKSRK

⁴⁷

EQKETTFYTL

⁵⁷

VCGLLVTDLL

⁶⁷

GTLLVSPVTI

⁷⁷

ATYMKGQWPG

⁸⁷

GQPLCEYSTF

⁹⁷

ILLFFSLSRL

¹⁰⁷

SIICAMSVER

¹¹⁷

YLAINHAYFY

¹²⁷

SHYVDKRLAG

¹³⁷

LTLFAVYASN

¹⁴⁷

VLFCALPNMG

¹⁵⁷

LGSSRLQYPD

¹⁶⁷

TWCFIDWTTQ

¹⁷⁷

VTAHAAYSYM

¹⁸⁷

YAGFSSFLIL

¹⁹⁷

ATVLCNVLVC

²⁰⁷

GALLRMHAGA

²⁶⁶

EIQMVILLIA

²⁷⁶

TSLVVLICSI

²⁸⁶

PLVVRVFVNQ

²⁹⁶

LYQPSLEREV

³⁰⁶

SKNPDLQAIR

³¹⁶

IASVNPILDP

³²⁶

WIYILLRKTV

³³⁶

LSKAIEKIKC

³⁴⁶

Residue

Distance (Å)

ILE23

4.214

PRO24

3.653

MET27

4.037

VAL72

3.904

THR76

2.755

TYR80

2.031

LEU99

3.303

THR168

3.445

Residue

Distance (Å)

TRP169

3.418

LEU312

3.617

ILE315

3.411

ARG316

2.554

ILE317

4.668

SER319

2.914

VAL320

3.227

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

Top

Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Pathway Affiliation

Biological Network Descriptors

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Olfactory receptor 1M1 (OR1M1)	PF13853	26.050 (31/119)	1.74E-04
Olfactory receptor 8A1 (OR8A1)	PF13853	22.689 (27/119)	3.00E-03

KEGG Pathway	Pathway ID	Affiliated Target
Neuroactive ligand-receptor interaction	hsa04080	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy
Inflammatory mediator regulation of TRP channels	hsa04750	Affiliated Target
Class: Organismal Systems => Sensory system	Pathway Hierarchy
Renin secretion	hsa04924	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy

Degree	1	Degree centrality	1.07E-04	Betweenness centrality	0.00E+00
Closeness centrality	2.01E-01	Radiality	1.35E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	3.10E+01	Topological coefficient	1.00E+00	Eccentricity	12
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 4 KEGG Pathways

Neuroactive ligand-receptor interaction

Inflammatory mediator regulation of TRP channels

Renin secretion

Pathways in cancer

NetPath Pathway

[+] 4 NetPath Pathways

FSH Signaling Pathway

IL2 Signaling Pathway

IL4 Signaling Pathway

TGF_beta_Receptor Signaling Pathway

Reactome

[+] 2 Reactome Pathways

Prostanoid ligand receptors

G alpha (s) signalling events

WikiPathways

[+] 6 WikiPathways

Prostaglandin Synthesis and Regulation

GPCRs, Class A Rhodopsin-like

Vitamin D Receptor Pathway

Small Ligand GPCRs

GPCR ligand binding

GPCR downstream signaling

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

Top

REF 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.

REF 2

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 3

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. (Ligand id: 3380).

REF 4

ClinicalTrials.gov (NCT00888680) Double-blind, Placebo-controlled Study of BGC20-1531 in Migraine. U.S. National Institutes of Health.

REF 5

REF 6

REF 7

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029996)

REF 8

ClinicalTrials.gov (NCT03696212) Open Label, Single Arm, Phase 1b/2 Study to Evaluate the Safety and Efficacy of Grapiprant (ARY-007) in Combination With Pembrolizumab in Patients With Advanced or Metastatic Post-PD-1/L1 Non-Small Cell Lung Cancer (NSCLC) Adenocarcinoma. U.S.National Institutes of Health.

REF 9

ClinicalTrials.gov (NCT04344795) Phase 1a/1b Study of TPST-1495 in Subjects With Solid Tumors. U.S. National Institutes of Health.

REF 10

ClinicalTrials.gov (NCT04975958) An Open-Label, Multicenter, Phase 1a Study of AN2025 and AN0025 in Double Combination With Atezolizumab and in Triple Combination With Atezolizumab in Patients With Advanced Solid Tumors. U.S.National Institutes of Health.

REF 11

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 12

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800039411)

REF 13

Stereocontrolled organocatalytic synthesis of prostaglandin PGF2alpha in seven steps. Nature. 2012 Sep 13;489(7415):278-81.

REF 14

REF 15

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800016907)

REF 16

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.

REF 17

An EP4 receptor agonist prevents indomethacin-induced closure of rat ductus arteriosus in vivo. Pediatr Res. 2004 Oct;56(4):586-90.

REF 18

Clinical pipeline report, company report or official report of Avarx.

REF 19

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.

REF 20

Molecular cloning and characterization of the four rat prostaglandin E2 prostanoid receptor subtypes. Eur J Pharmacol. 1997 Dec 11;340(2-3):227-41.

REF 21

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.

REF 22

Prostaglandin E2 EP4 agonist (ONO-4819) accelerates BMP-induced osteoblastic differentiation. Bone. 2007 Oct;41(4):543-8.

REF 23

Effects on improvement of blood flow in the chronically compressed cauda equina: comparison between a selective prostaglandin E receptor (EP4) agonist and a prostaglandin E1 derivate. Spine (Phila Pa1976). 2006 Apr 15;31(8):869-72.

REF 24

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.

REF 25

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.

REF 26

Comparison between two classes of selective EP(3) antagonists and their biological activities. Bioorg Med Chem Lett. 2006 Nov 1;16(21):5639-42.

REF 27

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.

REF 28

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.

REF 29

REF 30

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.

REF 31

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.

REF 32

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.

REF 33

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.

REF 34

Involvement of prostaglandin E receptor subtype EP(4) in colon carcinogenesis. Cancer Res. 2002 Jan 1;62(1):28-32.

REF 35

The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut. J Clin Invest. 2002 Apr;109(7):883-93.

REF 36

Host prostaglandin E(2)-EP3 signaling regulates tumor-associated angiogenesis and tumor growth. J Exp Med. 2003 Jan 20;197(2):221-32.

REF 37

Cryo-EM Structure of the Prostaglandin E Receptor EP4 Coupled to G Protein. Structure. 2021 Mar 4;29(3):252-260.e6.

REF 38

Ligand binding to human prostaglandin E receptor EP(4) at the lipid-bilayer interface. Nat Chem Biol. 2019 Jan;15(1):18-26.

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