Target Information
| Target General Information | Top | |||||
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| Target ID |
T62974
(Former ID: TTDC00034)
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| Target Name |
Somatostatin receptor type 4 (SSTR4)
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| Synonyms |
SSTR4; SS4R
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| Gene Name |
SSTR4
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Chronic pain ICD-11: MG30 | |||||
| 2 | Hepatitis virus infection [ICD-11: 1E50-1E51] | |||||
| Function |
Receptor for somatostatin-14. The activity of this receptor is mediated by G proteins which inhibits adenylyl cyclase. It is functionally coupled not only to inhibition of adenylate cyclase, but also to activation of both arachidonate release and mitogen-activated protein (MAP) kinase cascade. Mediates antiproliferative action of somatostatin in tumor cells.
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
MSAPSTLPPGGEEGLGTAWPSAANASSAPAEAEEAVAGPGDARAAGMVAIQCIYALVCLV
GLVGNALVIFVILRYAKMKTATNIYLLNLAVADELFMLSVPFVASSAALRHWPFGSVLCR AVLSVDGLNMFTSVFCLTVLSVDRYVAVVHPLRAATYRRPSVAKLINLGVWLASLLVTLP IAIFADTRPARGGQAVACNLQWPHPAWSAVFVVYTFLLGFLLPVLAIGLCYLLIVGKMRA VALRAGWQQRRRSEKKITRLVLMVVVVFVLCWMPFYVVQLLNLFVTSLDATVNHVSLILS YANSCANPILYGFLSDNFRRFFQRVLCLRCCLLEGAGGAEEEPLDYYATALKSKGGAGCM CPPLPCQQEALQPEPGRKRIPLTRTTTF 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) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | 177Lu-DOTATATE | Drug Info | Phase 2 | Hepatitis C virus infection | [3] | |
| 2 | CNTX-0290 | Drug Info | Phase 1 | Chronic pain | [4] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | FR-121196 | Drug Info | Terminated | Alzheimer disease | [5] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Inhibitor | [+] 22 Inhibitor drugs | + | ||||
| 1 | ODT-8 | Drug Info | [1] | |||
| 2 | 177Lu-DOTATATE | Drug Info | [6] | |||
| 3 | Ala11-SRIF-14-amide | Drug Info | [9] | |||
| 4 | Cytotoxin Peptide Conjugate | Drug Info | [12] | |||
| 5 | D-Trp8-SRIF-14 | Drug Info | [9] | |||
| 6 | Des-AA1,2,4,12,13-[D-Trp8]SRIF | Drug Info | [1] | |||
| 7 | Des-AA1,2,4,13-[D-Trp8]SRIF | Drug Info | [1] | |||
| 8 | Des-AA1,2,4,5,10,12,13-[D-Trp8]SRIF | Drug Info | [1] | |||
| 9 | Des-AA1,2,4,5-[D-Trp8]SRIF | Drug Info | [1] | |||
| 10 | Des-AA1,2,5,12,13-[D-Trp8,IAmp9]SRIF | Drug Info | [1] | |||
| 11 | Des-AA1,2,5,12,13-[D-Trp8]SRIF | Drug Info | [1] | |||
| 12 | Des-AA1,2,5-[D-Nal8,IAmp9,(NalphaMe)Thr12]SRIF | Drug Info | [13] | |||
| 13 | Des-AA1,2,5-[D-Trp8,Tyr11]SRIF | Drug Info | [13] | |||
| 14 | Des-AA1,2,5-[IAmp9,Tyr11]-SRIF | Drug Info | [13] | |||
| 15 | Des-AA1,5-[Tyr2,D-Trp8,(NalphaMe)IAmp9]Cbm-SRIF | Drug Info | [13] | |||
| 16 | Des-AA1,5-[Tyr2,D-Trp8,(NalphaMe)IAmp9]SRIF | Drug Info | [13] | |||
| 17 | Des-AA5-[D-Trp8]SRIF | Drug Info | [13] | |||
| 18 | Pyz11-D-Trp8-SRIF | Drug Info | [9] | |||
| 19 | Pyz6-D-Trp8-SRIF | Drug Info | [9] | |||
| 20 | Pyz7-D-Trp8-SRIF | Drug Info | [9] | |||
| 21 | SOMATOSTATIN | Drug Info | [16] | |||
| 22 | SRIF-28 | Drug Info | [18] | |||
| Agonist | [+] 6 Agonist drugs | + | ||||
| 1 | CNTX-0290 | Drug Info | [4] | |||
| 2 | beta3-tetrapeptide | Drug Info | [10] | |||
| 3 | CGP 23996 | Drug Info | [11] | |||
| 4 | L-803,087 | Drug Info | [14] | |||
| 5 | NNC269100 | Drug Info | [15] | |||
| 6 | SRIF-14 | Drug Info | [17] | |||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | FR-121196 | Drug Info | [7] | |||
| 2 | 99mTc-MIP-1407 | Drug Info | [8] | |||
| 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: (2S)-4-amino-N-[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]-2-[(4-methylnaphthalen-1-yl)sulfonylamino]butanamide | Ligand Info | |||||
| Structure Description | CryoEM structure of somatostatin receptor 4 (SSTR4) with Gi1 and J-2156 | PDB:7XMT | ||||
| Method | Electron microscopy | Resolution | 2.80 Å | Mutation | Yes | [19] |
| PDB Sequence |
GMVAIQCIYA
55 LVCLVGLVGN65 ALVIFVILRY75 AKMKTATNIY85 LLNLAVADEL95 FMLSVPFVAS 105 SAALRHWPFG115 SVLCRAVLSV125 DGLNMFTSVF135 CLTVLSVDRY145 VAVVHPLRAA 155 TYRRPSVAKL165 INLGVWLASL175 LVTLPIAIFA185 DTRPACNLQW202 PHPAWSAVFV 212 VYTFLLGFLL222 PVLAIGLCYL232 LIVGKMRAVA242 LRAGWQQRRR252 SEKKITRLVL 262 MFVVVFVLCW272 MPFYVVQLLN282 LFLDATVNHV295 SLILSYANSC305 ANPILYGFLS 315 DNFRR
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PHE96
4.337
SER99
4.025
VAL103
3.568
TRP112
3.544
VAL122
4.436
LEU123
3.553
ASP126
2.628
GLY127
4.185
MET130
3.472
PHE131
3.454
ILE181
3.268
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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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| Neuroactive ligand-receptor interaction | hsa04080 | Affiliated Target |
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| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| Degree | 1 | Degree centrality | 1.07E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.49E-01 | Radiality | 1.19E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 8.00E+00 | Topological coefficient | 1.00E+00 | Eccentricity | 14 |
| 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 Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Neuroactive ligand-receptor interaction | |||||
| Panther Pathway | [+] 2 Panther Pathways | + | ||||
| 1 | Heterotrimeric G-protein signaling pathway-Gi alpha and Gs alpha mediated pathway | |||||
| 2 | Heterotrimeric G-protein signaling pathway-Gq alpha and Go alpha mediated pathway | |||||
| Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
| 1 | Gastric Acid Production | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | Peptide ligand-binding receptors | |||||
| 2 | G alpha (i) signalling events | |||||
| WikiPathways | [+] 4 WikiPathways | + | ||||
| 1 | GPCRs, Class A Rhodopsin-like | |||||
| 2 | Peptide GPCRs | |||||
| 3 | GPCR ligand binding | |||||
| 4 | GPCR downstream signaling | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Somatostatin receptor 1 selective analogues: 3. Dicyclic peptides. J Med Chem. 2005 Jan 27;48(2):515-22. | |||||
| REF 2 | ClinicalTrials.gov (NCT04874636) Randomized, Placebo-Controlled, Phase 2 Clinical Trial to Evaluate LY3556050 for the Treatment of Chronic Low Back Pain. U.S.National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT01860742) Randomized Phase III of PRRT Versus Interferon. U.S. National Institutes of Health. | |||||
| REF 4 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 5 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001380) | |||||
| REF 6 | New Drug in Development Shows Improved Progression-Free Survival for Patients with Advanced Metastatic Midgut Neuroendocrine Tumors | |||||
| REF 7 | Role of somatostatin in the augmentation of hippocampal long-term potentiation by FR121196, a putative cognitive enhancer. Eur J Pharmacol. 1993 Sep 7;241(1):27-34. | |||||
| REF 8 | 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: 358). | |||||
| REF 9 | Replacement of Phe6, Phe7, and Phe11 of D-Trp8-somatostatin-14 with L-pyrazinylalanine. Predicted and observed effects on binding affinities at hSS... J Med Chem. 2005 Jun 16;48(12):4025-30. | |||||
| REF 10 | Beta(2)/beta(3)-di- and alpha/beta(3)-tetrapeptide derivatives as potent agonists at somatostatin sst(4) receptors. Naunyn Schmiedebergs Arch Pharmacol. 2003 Feb;367(2):95-103. | |||||
| REF 11 | Characterisation of human recombinant somatostatin receptors. 1. Radioligand binding studies. Naunyn Schmiedebergs Arch Pharmacol. 1999 Nov;360(5):488-99. | |||||
| REF 12 | An adjustable release rate linking strategy for cytotoxin-peptide conjugates. Bioorg Med Chem Lett. 2003 Mar 10;13(5):799-803. | |||||
| REF 13 | Somatostatin receptor 1 selective analogues: 2. N(alpha)-Methylated scan. J Med Chem. 2005 Jan 27;48(2):507-14. | |||||
| REF 14 | Rapid identification of subtype-selective agonists of the somatostatin receptor through combinatorial chemistry. Science. 1998 Oct 23;282(5389):737-40. | |||||
| REF 15 | Nonpeptide somatostatin agonists with sst4 selectivity: synthesis and structure-activity relationships of thioureas. J Med Chem. 1998 Nov 19;41(24):4693-705. | |||||
| REF 16 | Discovery of iodinated somatostatin analogues selective for hsst2 and hsst5 with excellent inhibition of growth hormone and prolactin release from ... J Med Chem. 2005 Oct 20;48(21):6643-52. | |||||
| REF 17 | Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2. Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10836-41. | |||||
| REF 18 | Novel octreotide dicarba-analogues with high affinity and different selectivity for somatostatin receptors. J Med Chem. 2010 Aug 26;53(16):6188-97. | |||||
| REF 19 | Structural insights into ligand recognition and selectivity of somatostatin receptors. Cell Res. 2022 Aug;32(8):761-772. | |||||
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