Target Information
| Target General Information | Top | |||||
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| Target ID |
T93788
(Former ID: TTDC00050)
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| Target Name |
Glucose-dependent insulinotropic receptor (GPR119)
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| Synonyms |
GPR119; G-protein coupled receptor 119
Click to Show/Hide
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| Gene Name |
GPR119
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Attention deficit hyperactivity disorder [ICD-11: 6A05] | |||||
| Function |
Receptor for the endogenous fatty-acid ethanolamide oleoylethanolamide (OEA) and lysophosphatidylcholine (LPC). Functions as a glucose-dependent insulinotropic receptor. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Seems to act through a G(s) mediated pathway.
Click to Show/Hide
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
MESSFSFGVILAVLASLIIATNTLVAVAVLLLIHKNDGVSLCFTLNLAVADTLIGVAISG
LLTDQLSSPSRPTQKTLCSLRMAFVTSSAAASVLTVMLITFDRYLAIKQPFRYLKIMSGF VAGACIAGLWLVSYLIGFLPLGIPMFQQTAYKGQCSFFAVFHPHFVLTLSCVGFFPAMLL FVFFYCDMLKIASMHSQQIRKMEHAGAMAGGYRSPRTPSDFKALRTVSVLIGSFALSWTP FLITGIVQVACQECHLYLVLERYLWLLGVGNSLLNPLIYAYWQKEVRLQLYHMALGVKKV LTSFLLFLSARNCGPERPRESSCHIVTISSSEFDG Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T16XQW | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Guanfacine extended release | Drug Info | Approved | Attention deficit hyperactivity disorder | [2] | |
| Clinical Trial Drug(s) | [+] 5 Clinical Trial Drugs | + | ||||
| 1 | DS-8500 | Drug Info | Phase 2 | Diabetic complication | [3] | |
| 2 | GSK1292263 | Drug Info | Phase 2 | Type-2 diabetes | [4] | |
| 3 | SAR-260093 | Drug Info | Phase 2 | Type-2 diabetes | [5] | |
| 4 | APD-597 | Drug Info | Phase 1 | Type-2 diabetes | [7], [8] | |
| 5 | BMS-903452 | Drug Info | Phase 1 | Type-2 diabetes | [9] | |
| Discontinued Drug(s) | [+] 2 Discontinued Drugs | + | ||||
| 1 | APD668 | Drug Info | Discontinued in Phase 1 | Type-2 diabetes | [10] | |
| 2 | PSN821 | Drug Info | Terminated | Type-2 diabetes | [11] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Agonist | [+] 33 Agonist drugs | + | ||||
| 1 | Guanfacine extended release | Drug Info | [1] | |||
| 2 | SAR-260093 | Drug Info | [14] | |||
| 3 | APD-597 | Drug Info | [15] | |||
| 4 | APD668 | Drug Info | [17] | |||
| 5 | PSN821 | Drug Info | [11] | |||
| 6 | (R)-N-oleoyltyrosinol | Drug Info | [18] | |||
| 7 | (S)-N-oleoyltyrosinol | Drug Info | [18] | |||
| 8 | 1-oleoyl glycerol | Drug Info | [19] | |||
| 9 | 1-palmitoyl-lysophosphatidylcholine | Drug Info | [20] | |||
| 10 | 1-stearoyl-lysophosphatidylcholine | Drug Info | [20] | |||
| 11 | 2-oleoyl glycerol | Drug Info | [19] | |||
| 12 | AR231453 | Drug Info | [21] | |||
| 13 | AS-1907417 | Drug Info | [1] | |||
| 14 | AS1269574 | Drug Info | [22] | |||
| 15 | LC34AD3 | Drug Info | [1] | |||
| 16 | lysophosphatidylethanolamine | Drug Info | [20] | |||
| 17 | lysophosphatidylinositol | Drug Info | [20] | |||
| 18 | N-oleoylethanolamide | Drug Info | [23] | |||
| 19 | oleoyl-lysophosphatidylcholine | Drug Info | [20] | |||
| 20 | PMID21273063C58 | Drug Info | [24] | |||
| 21 | PMID21310611C3 | Drug Info | [25] | |||
| 22 | PMID21444206C23 | Drug Info | [26] | |||
| 23 | PMID21444206C3a | Drug Info | [26] | |||
| 24 | PMID21444206C3j | Drug Info | [26] | |||
| 25 | PMID21536438C20f | Drug Info | [27] | |||
| 26 | PMID21536438C36j | Drug Info | [27] | |||
| 27 | PMID21939274C1 | Drug Info | [28] | |||
| 28 | PMID21939274C2 | Drug Info | [28] | |||
| 29 | PMID22545772C42 | Drug Info | [29] | |||
| 30 | PSN375963 | Drug Info | [30] | |||
| 31 | PSN632408 | Drug Info | [30] | |||
| 32 | RO-5212651 | Drug Info | [1] | |||
| 33 | SEA | Drug Info | [1] | |||
| Modulator | [+] 4 Modulator drugs | + | ||||
| 1 | DS-8500 | Drug Info | [12] | |||
| 2 | GSK1292263 | Drug Info | [13] | |||
| 3 | BMS-903452 | Drug Info | [16] | |||
| 4 | MBX-3254 | Drug Info | [1] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: APD668 | Ligand Info | |||||
| Structure Description | GPR119-Gs-APD668 complex | PDB:7XZ6 | ||||
| Method | Electron microscopy | Resolution | 2.80 Å | Mutation | No | [31] |
| PDB Sequence |
MESSFSFGVI
10 LAVLASLIIA20 TNTLVAVAVL30 LLIHKNDGVS40 LCFTLNLAVA50 DTLIGVAISG 60 LLTDQLSSPS70 RPTQKTLCSL80 RMAFVTSSAA90 ASVLTVMLIT100 FDRYLAIKQP 110 FRYLKIMSGF120 VAGACIAGLW130 LVSYLIGFLP140 LGIPMFQQTA150 YKGQCSFFAV 160 FHPHFVLTLS170 CVGFFPAMLL180 FVFFYCDMLK190 IASMHSQQIR200 KMEHAGAMAG 210 SDFKALRTVS228 VLIGSFALSW238 TPFLITGIVQ248 VACQECHLYL258 VLERYLWLLG 268 VGNSLLNPLI278 YAYWQKEVRL288 QLYHMALGVK298 KV
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PHE7
2.100
LEU11
2.687
ILE54
4.933
LEU61
2.437
GLN65
3.314
MET82
2.442
VAL85
2.574
THR86
2.706
ALA89
2.069
ALA90
2.138
VAL93
2.490
LEU94
2.245
VAL132
4.066
SER133
4.181
ILE136
2.279
CYS155
4.523
SER156
2.605
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| Ligand Name: (4r,7r,18e)-4,7-Dihydroxy-N,N,N-Trimethyl-10-Oxo-3,5,9-Trioxa-4-Phosphaheptacos-18-En-1-Aminium 4-Oxide | Ligand Info | |||||
| Structure Description | GPR119-Gs-LPC complex | PDB:7XZ5 | ||||
| Method | Electron microscopy | Resolution | 3.10 Å | Mutation | No | [31] |
| PDB Sequence |
MESSFSFGVI
10 LAVLASLIIA20 TNTLVAVAVL30 LLIHKNDGVS40 LCFTLNLAVA50 DTLIGVAISG 60 LLTDQLSSPS70 RPTQKTLCSL80 RMAFVTSSAA90 ASVLTVMLIT100 FDRYLAIKQP 110 FRYLKIMSGF120 VAGACIAGLW130 LVSYLIGFLP140 LGIPMFQQTA150 YKGQCSFFAV 160 FHPHFVLTLS170 CVGFFPAMLL180 FVFFYCDMLK190 IASMHSQQIR200 KMEHAGAMAG 210 SDFKALRTVS228 VLIGSFALSW238 TPFLITGIVQ248 VACQECHLYL258 VLERYLWLLG 268 VGNSLLNPLI278 YAYWQKEVRL288 QLYHMALGVK298 KV
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SER4
4.274
PHE7
2.421
LEU11
4.733
ILE58
4.505
LEU61
2.871
ASP64
4.836
GLN65
1.377
MET82
3.182
VAL85
2.373
THR86
2.751
ALA89
2.463
ALA90
2.373
VAL93
2.509
LEU94
2.482
VAL132
4.415
ILE136
2.912
GLN148
4.644
LYS152
4.221
GLN154
3.812
CYS155
3.224
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| 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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| cAMP signaling pathway | hsa04024 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Insulin secretion | hsa04911 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 1.78E-06 |
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| Closeness centrality | 1.77E-01 | Radiality | 1.29E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 1.00E+01 | Topological coefficient | 6.00E-01 | Eccentricity | 13 |
| 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 | ||
| 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 Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | cAMP signaling pathway | |||||
| 2 | Insulin secretion | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Incretin Synthesis, Secretion, and Inactivation | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | 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: 126). | |||||
| REF 2 | Emerging drugs for attention-deficit/hyperactivity disorder. Expert Opin Emerg Drugs. 2007 Sep;12(3):423-34. | |||||
| REF 3 | ClinicalTrials.gov (NCT02222350) Phase 2 Study of DS-8500a in Patients With Type 2 Diabetes. U.S. National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT01218204) A Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Administering Multiple Oral Doses of GSK1292263 Alone and With Atorvastatin.U.S. National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT01035879) Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of MBX-2982 Administered Daily for 4 Weeks as Monotherapy in Patients With Type 2 Diabetes.U.S. National Institutes of Health. | |||||
| REF 6 | ClinicalTrials.gov (NCT03646721) A Study to Evaluate the Safety, Tolerability, PK and PD of DA-1241 in Healthy Male Subjects and Subjects With T2DM. U.S. National Institutes of Health. | |||||
| 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: 5727). | |||||
| REF 8 | ClinicalTrials.gov (NCT00910923) A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of JNJ-38431055 in Healthy Male Volunteers. U.S. National Institutes of Health. | |||||
| REF 9 | ClinicalTrials.gov (NCT01240980) Safety Study of BMS-903452 in Healthy Subjects (Panel 1-7) & Relative Bioavailability of the Crystalline and Amorphous Forms of BMS-903452 [Panels 4, 6, 11 & 12(Part A)], and Subjects With Type 2 Diabetes Mellitus (Part B). U.S. National Institutes of Health. | |||||
| REF 10 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800023882) | |||||
| REF 11 | Clinical pipeline report, company report or official report of Astellas Pharma (2011). | |||||
| REF 12 | Addressing Unmet Medical Needs in Type 2 Diabetes: A Narrative Review of Drugs under Development. Curr Diabetes Rev. 2015 March; 11(1): 17-31. | |||||
| REF 13 | Gut hormone pharmacology of a novel GPR119 agonist (GSK1292263), metformin, and sitagliptin in type 2 diabetes mellitus: results from two randomized studies.PLoS One.2014 Apr 3;9(4):e92494. | |||||
| REF 14 | GPR119 agonists for the treatment of type 2 diabetes. Expert Opin Ther Pat. 2009 Oct;19(10):1339-59. | |||||
| REF 15 | Discovery of a second generation agonist of the orphan G-protein coupled receptor GPR119 with an improved profile. Bioorg Med Chem Lett. 2012 Feb 15;22(4):1750-5. | |||||
| REF 16 | Discovery of 5-chloro-4-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (BMS-903452), an antidiabetic clinical candidate targeting GPR119. J MedChem. 2014 Sep 25;57(18):7499-508. | |||||
| REF 17 | Announces Initiation of Phase 1 Clinical Trial of Arena Type 2 Diabetes Drug Candidate in Collaboration With Ortho-McNeil. Arena Pharmaceuticals, Inc. FEBRUARY 07, 2006. | |||||
| REF 18 | N-oleoyldopamine enhances glucose homeostasis through the activation of GPR119. Mol Endocrinol. 2010 Jan;24(1):161-70. | |||||
| REF 19 | 2-Oleoyl glycerol is a GPR119 agonist and signals GLP-1 release in humans. J Clin Endocrinol Metab. 2011 Sep;96(9):E1409-17. | |||||
| REF 20 | Lysophosphatidylcholine enhances glucose-dependent insulin secretion via an orphan G-protein-coupled receptor. Biochem Biophys Res Commun. 2005 Jan 28;326(4):744-51. | |||||
| REF 21 | A role for beta-cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucose-dependent insulin release. Endocrinology. 2007 Jun;148(6):2601-9. | |||||
| REF 22 | Identification of a novel GPR119 agonist, AS1269574, with in vitro and in vivo glucose-stimulated insulin secretion. Biochem Biophys Res Commun. 2010 Sep 24;400(3):437-41. | |||||
| REF 23 | Screening beta-arrestin recruitment for the identification of natural ligands for orphan G-protein-coupled receptors. J Biomol Screen. 2013 Jun;18(5):599-609. | |||||
| REF 24 | Design of potent and selective GPR119 agonists for type II diabetes. Bioorg Med Chem Lett. 2011 May 1;21(9):2665-9. | |||||
| REF 25 | Design and evaluation of a 2-(2,3,6-trifluorophenyl)acetamide derivative as an agonist of the GPR119 receptor. Bioorg Med Chem Lett. 2011 Mar 1;21(5):1306-9. | |||||
| REF 26 | Discovery of fused bicyclic agonists of the orphan G-protein coupled receptor GPR119 with in vivo activity in rodent models of glucose control. Bioorg Med Chem Lett. 2011 May 15;21(10):3134-41. | |||||
| REF 27 | Discovery of a nortropanol derivative as a potent and orally active GPR119 agonist for type 2 diabetes. Bioorg Med Chem Lett. 2011 Jun 1;21(11):3290-6. | |||||
| REF 28 | Oxidative metabolism of a quinoxaline derivative by xanthine oxidase in rodent plasma. Chem Res Toxicol. 2011 Dec 19;24(12):2207-16. | |||||
| REF 29 | Use of small-molecule crystal structures to address solubility in a novel series of G protein coupled receptor 119 agonists: optimization of a lead and in vivo evaluation. J Med Chem. 2012 Jun 14;55(11):5361-79. | |||||
| REF 30 | Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab. 2006 Mar;3(3):167-75. | |||||
| REF 31 | Structural identification of lysophosphatidylcholines as activating ligands for orphan receptor GPR119. Nat Struct Mol Biol. 2022 Sep;29(9):863-870. | |||||
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