Target Information
| Target General Information | Top | |||||
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| Target ID |
T99816
(Former ID: TTDC00230)
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| Target Name |
Gastrin-releasing peptide receptor (GRPR)
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| Synonyms |
GRPR; GRP-preferring bombesin receptor; GRP-R; Bombesin/gastrin-releasing peptide receptor
Click to Show/Hide
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| Gene Name |
GRPR
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Irritable bowel syndrome [ICD-11: DD91] | |||||
| 2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| 3 | Breast cancer [ICD-11: 2C60-2C6Y] | |||||
| Function |
Receptor for gastrin-releasing peptide (GRP). Signals via association with G proteins that activate a phosphatidylinositol-calcium second messenger system, resulting in Akt phosphorylation. Contributes to the regulation of food intake. Contributes to the perception of prurient stimuli and transmission of itch signals in the spinal cord that promote scratching behavior, but does not play a role in the perception of pain. Contributes primarily to nonhistaminergic itch sensation. Contributes to long-term fear memory, but not normal spatial memory.
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
MALNDCFLLNLEVDHFMHCNISSHSADLPVNDDWSHPGILYVIPAVYGVIILIGLIGNIT
LIKIFCTVKSMRNVPNLFISSLALGDLLLLITCAPVDASRYLADRWLFGRIGCKLIPFIQ LTSVGVSVFTLTALSADRYKAIVRPMDIQASHALMKICLKAAFIWIISMLLAIPEAVFSD LHPFHEESTNQTFISCAPYPHSNELHPKIHSMASFLVFYVIPLSIISVYYYFIAKNLIQS AYNLPVEGNIHVKKQIESRKRLAKTVLVFVGLFAFCWLPNHVIYLYRSYHYSEVDTSMLH FVTSICARLLAFTNSCVNPFALYLLSKSFRKQFNTQLLCCQPGLIIRSHSTGRSTTCMTS LKSTNPSVATFSLINGNICHERYV Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 5 Clinical Trial Drugs | + | ||||
| 1 | 177Lu-labelled NeoBOMB1 | Drug Info | Phase 2 | Solid tumour/cancer | [2] | |
| 2 | ASP-7147 | Drug Info | Phase 2 | Irritable bowel syndrome | [3] | |
| 3 | RC-3095 | Drug Info | Phase 2 | Solid tumour/cancer | [4], [5], [6] | |
| 4 | 177-Lu-NeoB | Drug Info | Phase 1/2 | Solid tumour/cancer | [7] | |
| 5 | 177Lu-AMBA | Drug Info | Phase 1 | Breast cancer | [8] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | BIM-26226 | Drug Info | Discontinued in Phase 1 | Solid tumour/cancer | [9] | |
| Mode of Action | [+] 4 Modes of Action | + | ||||
| Antagonist | [+] 7 Antagonist drugs | + | ||||
| 1 | ASP-7147 | Drug Info | [1] | |||
| 2 | 177-Lu-NeoB | Drug Info | [10] | |||
| 3 | 177Lu-labelled RM2 | Drug Info | [16] | |||
| 4 | bantag-1 | Drug Info | [17] | |||
| 5 | kuwanon H | Drug Info | [19] | |||
| 6 | PD 168368 | Drug Info | [20] | |||
| 7 | PD 176252 | Drug Info | [21] | |||
| Inhibitor | [+] 19 Inhibitor drugs | + | ||||
| 1 | RC-3095 | Drug Info | [11] | |||
| 2 | (CH3)CCO-His-Trp-Ala-Val-Gly-His-Leu-Met-NH2 | Drug Info | [14] | |||
| 3 | (D)Phe-Gln-Trp-Ala-Val-Gly-His-Leu-Leu-NH2 | Drug Info | [15] | |||
| 4 | Ac-His-Trp-Ala-Val-Ala-His-Leu-Met-NH2 | Drug Info | [14] | |||
| 5 | Ac-His-Trp-Ala-Val-D-Ala-His-Leu-Met-NH2 | Drug Info | [14] | |||
| 6 | Ac-His-Trp-Ala-Val-Gly-His-Leu-Met-NH2 | Drug Info | [14] | |||
| 7 | JMV 1535 | Drug Info | [15] | |||
| 8 | JMV 1693 | Drug Info | [15] | |||
| 9 | JMV 1719 | Drug Info | [15] | |||
| 10 | JMV 1799 | Drug Info | [15] | |||
| 11 | JMV 1801 | Drug Info | [15] | |||
| 12 | JMV 1802 | Drug Info | [15] | |||
| 13 | JMV 1803 | Drug Info | [15] | |||
| 14 | JMV 1813 | Drug Info | [15] | |||
| 15 | [(N4-Bzdig)0,Nle14]BB(7-14) | Drug Info | [23] | |||
| 16 | [(N4-Bzdig)0]BB(7-14) | Drug Info | [23] | |||
| 17 | [N40,Pro1,Tyr4,Nle 14]BB | Drug Info | [23] | |||
| 18 | [N40,Pro1,Tyr4]BB | Drug Info | [23] | |||
| 19 | [Tyr4]Bombesin | Drug Info | [23] | |||
| Agonist | [+] 5 Agonist drugs | + | ||||
| 1 | 177Lu-AMBA | Drug Info | [12] | |||
| 2 | bombesin | Drug Info | [18] | |||
| 3 | MK-5046 | Drug Info | [17] | |||
| 4 | neuromedin B | Drug Info | [18] | |||
| 5 | ranatensin | Drug Info | [22] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | BIM-26226 | Drug Info | [13] | |||
| 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 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
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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 | ||
| Neuroactive ligand-receptor interaction | hsa04080 | Affiliated Target |
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| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 2.86E-04 | Radiality | 9.56E-03 | Clustering coefficient | 1.00E+00 |
| Neighborhood connectivity | 4.00E+00 | Topological coefficient | 1.00E+00 | Eccentricity | 2 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| 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 | ||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | Calcium signaling pathway | |||||
| 2 | Neuroactive ligand-receptor interaction | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | Peptide ligand-binding receptors | |||||
| 2 | G alpha (q) signalling events | |||||
| WikiPathways | [+] 3 WikiPathways | + | ||||
| 1 | GPCRs, Class A Rhodopsin-like | |||||
| 2 | Peptide GPCRs | |||||
| 3 | GPCRs, Other | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Astellas and Drais Partner To Develop Third Astellas Compound through Tacurion | |||||
| REF 2 | ClinicalTrials.gov (NCT03724253) [68Ga]-NeoBOMB1 Imaging in Patients With Malignancies Known to Overexpress Gastrin Releasing Peptide Receptor (GRPR) (NeoFIND). U.S. National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT01896583) A Phase 2 Pilot Study to Assess ASP7147 in Patients With Diarrhea Predominant Irritable Bowel Syndrome (IBS-D). U.S. National Institutes of Health. | |||||
| REF 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. (Ligand id: 6183). | |||||
| REF 5 | Protective effect of RC-3095, an antagonist of the gastrin-releasing peptide receptor, in experimental arthritis. Arthritis Rheum. 2011 Oct;63(10):2956-65. | |||||
| REF 6 | Gastrin-releasing peptide receptor (GRPR) mediates chemotaxis in neutrophils. Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):547-52. | |||||
| REF 7 | ClinicalTrials.gov (NCT03872778) [177Lu]-NeoB in Patients With Advanced Solid Tumors and With [68Ga]-NeoB Lesion Uptake (NeoRay). U.S. National Institutes of Health. | |||||
| 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 800029232) | |||||
| REF 9 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004166) | |||||
| REF 10 | 68Ga/177Lu-NeoBOMB1, a Novel Radiolabeled GRPR Antagonist for Theranostic Use in Oncology. J Nucl Med. 2017 Feb;58(2):293-299. | |||||
| REF 11 | Lipid modification of GRN163, an N3'-->P5' thio-phosphoramidate oligonucleotide, enhances the potency of telomerase inhibition. Oncogene. 2005 Aug 4;24(33):5262-8. | |||||
| REF 12 | Multimodality imaging and preclinical evaluation of 177Lu-AMBA for human prostate tumours in a murine model. Anticancer Res. 2010 Oct;30(10):4039-48. | |||||
| REF 13 | Effect of the gastrin-releasing peptide antagonist BIM 26226 and lanreotide on an acinar pancreatic carcinoma. Eur J Pharmacol. 1998 Apr 17;347(1):77-86. | |||||
| REF 14 | Gastrin releasing peptide antagonists with improved potency and stability. J Med Chem. 1991 Jul;34(7):2102-7. | |||||
| REF 15 | Synthesis and biological evaluation of bombesin constrained analogues. J Med Chem. 2000 Jun 15;43(12):2356-61. | |||||
| REF 16 | Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nat Rev Drug Discov. 2020 Sep;19(9):589-608. | |||||
| REF 17 | Comparative pharmacology of bombesin receptor subtype-3, nonpeptide agonist MK-5046, a universal peptide agonist, and peptide antagonist Bantag-1 for human bombesin receptors. J Pharmacol Exp Ther. 2013 Oct;347(1):100-16. | |||||
| REF 18 | Expression and characterization of cloned human bombesin receptors. Mol Pharmacol. 1995 Jan;47(1):10-20. | |||||
| REF 19 | Non-peptide bombesin receptor antagonists, kuwanon G and H, isolated from mulberry. Biochem Biophys Res Commun. 1995 Aug 15;213(2):594-9. | |||||
| REF 20 | Comparative pharmacology of the nonpeptide neuromedin B receptor antagonist PD 168368. J Pharmacol Exp Ther. 1999 Sep;290(3):1202-11. | |||||
| REF 21 | PD 176252--the first high affinity non-peptide gastrin-releasing peptide (BB2) receptor antagonist. Bioorg Med Chem Lett. 1998 Sep 22;8(18):2589-94. | |||||
| REF 22 | Pharmacology and cell biology of the bombesin receptor subtype 4 (BB4-R). Biochemistry. 1999 Jun 1;38(22):7307-20. | |||||
| REF 23 | Potent bombesin-like peptides for GRP-receptor targeting of tumors with 99mTc: a preclinical study. J Med Chem. 2005 Jan 13;48(1):100-10. | |||||
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