Target Information
| Target General Information | Top | |||||
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| Target ID |
T85467
(Former ID: TTDC00037)
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| Target Name |
Prostaglandin E2 receptor EP3 (PTGER3)
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| Synonyms |
Prostanoid EP3 receptor; Prostaglandin E2 receptor EP3 subtype; PGE2-R; PGE2 receptor EP3 subtype; PGE receptor, EP3 subtype; PGE receptor EP3 subtype
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| Gene Name |
PTGER3
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Glaucoma [ICD-11: 9C61] | |||||
| 2 | Transplanted organ/tissue [ICD-11: QB63] | |||||
| 3 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| 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).
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
MKETRGYGGDAPFCTRLNHSYTGMWAPERSAEARGNLTRPPGSGEDCGSVSVAFPITMLL
TGFVGNALAMLLVSRSYRRRESKRKKSFLLCIGWLALTDLVGQLLTTPVVIVVYLSKQRW EHIDPSGRLCTFFGLTMTVFGLSSLFIASAMAVERALAIRAPHWYASHMKTRATRAVLLG VWLAVLAFALLPVLGVGQYTVQWPGTWCFISTGRGGNGTSSSHNWGNLFFASAFAFLGLL ALTVTFSCNLATIKALVSRCRAKATASQSSAQWGRITTETAIQLMGIMCVLSVCWSPLLI MMLKMIFNQTSVEHCKTHTEKQKECNFFLIAVRLASLNQILDPWVYLLLRKILLRKFCQI RYHTNNYASSSTSLPCQCSSTLMWSDHLER Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T84PM0 | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | PGF2alpha | Drug Info | Clinical trial | Solid tumour/cancer | [4] | |
| Discontinued Drug(s) | [+] 2 Discontinued Drugs | + | ||||
| 1 | DG041 | Drug Info | Discontinued in Phase 2 | Peripheral vascular disease | [5], [6] | |
| 2 | GR-63799X | Drug Info | Discontinued in Phase 1 | Asthma | [7], [8] | |
| Mode of Action | [+] 4 Modes of Action | + | ||||
| Agonist | [+] 15 Agonist drugs | + | ||||
| 1 | PGF2alpha | Drug Info | [9] | |||
| 2 | 11-deoxy-PGE1 | Drug Info | [13] | |||
| 3 | butaprost (free acid form) | Drug Info | [15] | |||
| 4 | cicaprost | Drug Info | [9] | |||
| 5 | cloprostenol | Drug Info | [15] | |||
| 6 | fluprostenol | Drug Info | [15] | |||
| 7 | isocarbacyclin | Drug Info | [9] | |||
| 8 | M&B 28767 | Drug Info | [9] | |||
| 9 | ONO-8713 | Drug Info | [13] | |||
| 10 | ONO-AE-248 | Drug Info | [19] | |||
| 11 | ONO-AE1-329 | Drug Info | [20] | |||
| 12 | PGD2 | Drug Info | [13] | |||
| 13 | SC46275 | Drug Info | [25] | |||
| 14 | STA2 | Drug Info | [9] | |||
| 15 | U46619 | Drug Info | [15] | |||
| Antagonist | [+] 8 Antagonist drugs | + | ||||
| 1 | DG041 | Drug Info | [10], [11] | |||
| 2 | AH6809 | Drug Info | [15] | |||
| 3 | L-798,106 | Drug Info | [17] | |||
| 4 | Molecule 21 | Drug Info | [18] | |||
| 5 | ONO-AE2-227 | Drug Info | [21] | |||
| 6 | ONO-AE3-208 | Drug Info | [22] | |||
| 7 | ONO-AE3-240 | Drug Info | [23] | |||
| 8 | ONO-AE5-599 | Drug Info | [24] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | GR-63799X | Drug Info | [12] | |||
| Inhibitor | [+] 3 Inhibitor drugs | + | ||||
| 1 | 3-(2-(4-methoxycinnamyl)phenyl)acrylic acid | Drug Info | [14] | |||
| 2 | 3-(2-cinnamylphenyl)acrylic acid | Drug Info | [14] | |||
| 3 | FR-181157 | Drug Info | [16] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Different Human System Profiles of Target | Top |
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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 Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
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).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Calcium signaling pathway | hsa04020 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| cAMP signaling pathway | hsa04024 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Neuroactive ligand-receptor interaction | hsa04080 | Affiliated Target |
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| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| Regulation of lipolysis in adipocytes | hsa04923 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "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 | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 5 KEGG Pathways | + | ||||
| 1 | Calcium signaling pathway | |||||
| 2 | cAMP signaling pathway | |||||
| 3 | Neuroactive ligand-receptor interaction | |||||
| 4 | Regulation of lipolysis in adipocytes | |||||
| 5 | Pathways in cancer | |||||
| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | IL2 Signaling Pathway | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | Prostanoid ligand receptors | |||||
| 2 | G alpha (i) signalling events | |||||
| WikiPathways | [+] 5 WikiPathways | + | ||||
| 1 | Prostaglandin Synthesis and Regulation | |||||
| 2 | GPCRs, Class A Rhodopsin-like | |||||
| 3 | Small Ligand GPCRs | |||||
| 4 | GPCR ligand binding | |||||
| 5 | GPCR downstream signaling | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| 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 | 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. | |||||
| REF 4 | Stereocontrolled organocatalytic synthesis of prostaglandin PGF2alpha in seven steps. Nature. 2012 Sep 13;489(7415):278-81. | |||||
| REF 5 | 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: 5822). | |||||
| REF 6 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015910) | |||||
| REF 7 | 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: 1937). | |||||
| REF 8 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003508) | |||||
| REF 9 | 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 10 | BAY x 1005 attenuates atherosclerosis in apoE/LDLR - double knockout mice. J Physiol Pharmacol. 2007 Sep;58(3):583-8. | |||||
| REF 11 | Effects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trial. JAMA. 2005 May 11;293(18):2245-56. | |||||
| REF 12 | 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. | |||||
| REF 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. | |||||
| REF 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. | |||||
| REF 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. | |||||
| REF 16 | Metabolism investigation leading to novel drug design: orally active prostacyclin mimetics. Part 4. Bioorg Med Chem Lett. 2005 Jul 1;15(13):3284-7. | |||||
| REF 17 | 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. | |||||
| REF 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: 342). | |||||
| REF 19 | Selective activation of the prostanoid EP(3) receptor reduces myocardial infarct size in rodents. Arterioscler Thromb Vasc Biol. 1999 Sep;19(9):2141-7. | |||||
| REF 20 | 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 21 | Involvement of prostaglandin E receptor subtype EP(4) in colon carcinogenesis. Cancer Res. 2002 Jan 1;62(1):28-32. | |||||
| REF 22 | 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 23 | Host prostaglandin E(2)-EP3 signaling regulates tumor-associated angiogenesis and tumor growth. J Exp Med. 2003 Jan 20;197(2):221-32. | |||||
| REF 24 | Involvement of prostaglandin E receptor EP3 subtype in duodenal bicarbonate secretion in rats. Life Sci. 2007 Jun 6;80(26):2446-53. | |||||
| REF 25 | 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. | |||||
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