Target Information
| Target General Information | Top | |||||
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| Target ID |
T99338
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| Target Name |
Stimulator of interferon genes protein (TMEM173)
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| Synonyms |
Mediator of IRF3 activation; Endoplasmic reticulum interferon stimulator; ERIS
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| Gene Name |
TMEM173
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 5 Target-related Diseases | + | ||||
| 1 | Head and neck cancer [ICD-11: 2D42] | |||||
| 2 | Lymphoma [ICD-11: 2A80-2A86] | |||||
| 3 | Melanoma [ICD-11: 2C30] | |||||
| 4 | Metastatic lymph node neoplasm [ICD-11: 2D60] | |||||
| 5 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Facilitator of innate immune signaling that acts as a sensor of cytosolic DNA from bacteria and viruses and promotes the production of type I interferon (IFN-alpha and IFN-beta). Innate immune response is triggered in response to non-CpG double-stranded DNA from viruses and bacteria delivered to the cytoplasm. Acts by recognizing and binding cyclic di-GMP (c-di-GMP), a second messenger produced by bacteria, and cyclic GMP-AMP (cGAMP), a messenger produced in response to DNA virus in the cytosol: upon binding of c-di-GMP or cGAMP, autoinhibition is alleviated and TMEM173/STING is able to activate both NF-kappa-B and IRF3 transcription pathways to induce expression of type I interferon and exert a potent anti-viral state. May be involved in translocon function, the translocon possibly being able to influence the induction of type I interferons. May be involved in transduction of apoptotic signals via its association with the major histocompatibility complex class II (MHC-II). Mediates death signaling via activation of the extracellular signal-regulated kinase (ERK) pathway. Essential for the induction of IFN-beta in response to human herpes simplex virus 1 (HHV-1) infection. Exhibits 2',3' phosphodiester linkage-specific ligand recognition. Can bind both 2'-3' linked cGAMP and 3'-3' linked cGAMP but is preferentially activated by 2'-3' linked cGAMP (PubMed:26300263).
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| BioChemical Class |
TMEM173 family
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| UniProt ID | ||||||
| Sequence |
MPHSSLHPSIPCPRGHGAQKAALVLLSACLVTLWGLGEPPEHTLRYLVLHLASLQLGLLL
NGVCSLAEELRHIHSRYRGSYWRTVRACLGCPLRRGALLLLSIYFYYSLPNAVGPPFTWM LALLGLSQALNILLGLKGLAPAEISAVCEKGNFNVAHGLAWSYYIGYLRLILPELQARIR TYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDHAGIKDRVY SNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCRTLEDILA DAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGSLKTSAVPSTSTMSQE PELLISGMEKPLPLRTDFS Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T50C67 | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 15 Clinical Trial Drugs | + | ||||
| 1 | ADU- S100 | Drug Info | Phase 2 | Head and neck cancer | [2] | |
| 2 | ADU-S100 | Drug Info | Phase 2 | Head and neck cancer | [3] | |
| 3 | MK-1454 | Drug Info | Phase 2 | Squamous head and neck cell carcinom | [4] | |
| 4 | IMSA101 | Drug Info | Phase 1/2 | Solid tumour/cancer | [5] | |
| 5 | A296 | Drug Info | Phase 1 | Aggressive cancer | [6] | |
| 6 | BMS-986301 | Drug Info | Phase 1 | Solid tumour/cancer | [7] | |
| 7 | E7766 | Drug Info | Phase 1 | Solid tumour/cancer | [8] | |
| 8 | GSK3745417 | Drug Info | Phase 1 | Solid tumour/cancer | [9] | |
| 9 | MK-2118 | Drug Info | Phase 1 | Lymphoma | [1] | |
| 10 | SB 11285 | Drug Info | Phase 1 | Melanoma | [10] | |
| 11 | SNX281 | Drug Info | Phase 1 | Lymphoma | [11] | |
| 12 | SYNB1891 | Drug Info | Phase 1 | Lymphoma | [12] | |
| 13 | TAK-500 | Drug Info | Phase 1 | Aggressive cancer | [13] | |
| 14 | TAK-676 | Drug Info | Phase 1 | Solid tumour/cancer | [14] | |
| 15 | XMT-2056 | Drug Info | Phase 1 | Aggressive cancer | [15] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Agonist | [+] 15 Agonist drugs | + | ||||
| 1 | ADU- S100 | Drug Info | [16] | |||
| 2 | MK-1454 | Drug Info | [17] | |||
| 3 | IMSA101 | Drug Info | [18] | |||
| 4 | A296 | Drug Info | [6] | |||
| 5 | BMS-986301 | Drug Info | [19] | |||
| 6 | E7766 | Drug Info | [20] | |||
| 7 | GSK3745417 | Drug Info | [21] | |||
| 8 | MK-2118 | Drug Info | [22] | |||
| 9 | SB 11285 | Drug Info | [23] | |||
| 10 | SYNB1891 | Drug Info | [25] | |||
| 11 | TAK-500 | Drug Info | [13] | |||
| 12 | TAK-676 | Drug Info | [26] | |||
| 13 | XMT-2056 | Drug Info | [27] | |||
| 14 | C-176 | Drug Info | [28] | |||
| 15 | C-178 | Drug Info | [29] | |||
| Activator | [+] 1 Activator drugs | + | ||||
| 1 | ADU-S100 | Drug Info | [1] | |||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | SNX281 | Drug Info | [24] | |||
| 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: Vadimezan | Ligand Info | |||||
| Structure Description | Crystal structure of hSTING(group2) in complex with DMXAA | PDB:4QXO | ||||
| Method | X-ray diffraction | Resolution | 1.88 Å | Mutation | Yes | [30] |
| PDB Sequence |
SVAHGLAWSY
163 YIGYLRLILP173 ELQARIRTYN183 QHYNNLLRGA193 VSQRLYILLP203 LDCGVPDNLS 213 MADPNIRFRD223 MLPQQNIDRA233 GIKNRVYSNS243 VYELLENGQR253 AGTCVLEYAT 263 PLQTLFAMSQ273 YSQAGFSRED283 RLEQAKLFCR293 TLEDILADAP303 ESQNNCRLIA 313 YQEPADDSSF323 SLSQEVLRHL333 RQ
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: L-serine-O-phosphate | Ligand Info | |||||
| Structure Description | phospho-STING binding to adaptor protein complex-1 | PDB:7R4H | ||||
| Method | Electron microscopy | Resolution | 2.34 Å | Mutation | Yes | [31] |
| PDB Sequence |
QEPELLIG
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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 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).
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 Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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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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| NOD-like receptor signaling pathway | hsa04621 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| RIG-I-like receptor signaling pathway | hsa04622 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Cytosolic DNA-sensing pathway | hsa04623 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Degree | 7 | Degree centrality | 7.52E-04 | Betweenness centrality | 9.82E-06 |
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| Closeness centrality | 2.11E-01 | Radiality | 1.37E+01 | Clustering coefficient | 5.24E-01 |
| Neighborhood connectivity | 1.80E+01 | Topological coefficient | 2.14E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 6 KEGG Pathways | + | ||||
| 1 | NOD-like receptor signaling pathway | |||||
| 2 | RIG-I-like receptor signaling pathway | |||||
| 3 | Cytosolic DNA-sensing pathway | |||||
| 4 | Human cytomegalovirus infection | |||||
| 5 | Herpes simplex virus 1 infection | |||||
| 6 | Human immunodeficiency virus 1 infection | |||||
| References | Top | |||||
|---|---|---|---|---|---|---|
| REF 1 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 2 | ClinicalTrials.gov (NCT03937141) Efficacy and Safety Trial of ADU-S100 and Pembrolizumab in Head and Neck Cancer. U.S. National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT03937141) Efficacy and Safety Trial of ADU-S100 and Pembrolizumab in Head and Neck Cancer. U.S. National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT04220866) Study of Intratumoral (IT) MK-1454 in Combination With Intravenous (IV) Pembrolizumab (MK-3475) Compared to IV Pembrolizumab Alone as the First Line Treatment of Metastatic or Unresectable, Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC) (MK-1454-002). U.S. National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT04020185) Safety and Efficacy Study of IMSA101 in Refractory Malignancies. U.S. National Institutes of Health. | |||||
| REF 6 | Clinical pipeline report, company report or official report of Klus Pharma | |||||
| REF 7 | ClinicalTrials.gov (NCT03956680) An Investigational Immunotherapy Study of BMS-986301 Alone or in Combination With Nivolumab, and Ipilimumab in Participants With Advanced Solid Cancers. U.S. National Institutes of Health. | |||||
| REF 8 | ClinicalTrials.gov (NCT04144140) Study of Intratumorally Administered Stimulator of Interferon Genes (STING) Agonist E7766 in Participants With Advanced Solid Tumors or Lymphomas - INSTAL-101. U.S. National Institutes of Health. | |||||
| REF 9 | ClinicalTrials.gov (NCT03843359) Phase 1 First Time in Humans (FTIH), Open Label Study of GSK3745417 Administered to Subjects With Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 10 | ClinicalTrials.gov (NCT04096638) Evaluating Safety and Efficacy of SB 11285 Alone and in Combination With Atezolizumab in Patients With Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 11 | ClinicalTrials.gov (NCT04609579) Study of SNX281 in Subjects With Advanced Solid Tumors and Lymphoma. U.S. National Institutes of Health. | |||||
| REF 12 | ClinicalTrials.gov (NCT04167137) Safety and Tolerability of SYNB1891 Injection Alone or in Combination With Atezolizumab in Adult Subjects. U.S. National Institutes of Health. | |||||
| REF 13 | ClinicalTrials.gov (NCT05070247) An Open-label, Dose Escalation and Expansion, Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Antitumor Activity of TAK-500, a Novel Stimulator of Interferon Genes Agonist, as a Single Agent and in Combination With Pembrolizumab in Adult Patients With Select Locally Advanced or Metastatic Solid Tumors. U.S.National Institutes of Health. | |||||
| REF 14 | ClinicalTrials.gov (NCT04420884) A Study of TAK-676 and TAK-676 in Combination With Pembrolizumab in Adults With Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 15 | ClinicalTrials.gov (NCT05514717) A Phase 1, First-in-Human, Dose Escalation and Expansion, Multicenter Study of XMT-2056 in Participants With Advanced/Recurrent Solid Tumors That Express HER2. U.S.National Institutes of Health. | |||||
| REF 16 | Magnitude of Therapeutic STING Activation Determines CD8 + T Cell-Mediated Anti-tumor Immunity. Cell Rep. 2018 Dec 11;25(11):3074-3085.e5. | |||||
| REF 17 | National Cancer Institute Drug Dictionary (drug name MK1454). | |||||
| REF 18 | Clinical pipeline report, company report or official report of ImmuneSensor Therapeutics. | |||||
| REF 19 | Challenges and Opportunities in the Clinical Development of STING Agonists for Cancer Immunotherapy. J Clin Med. 2020 Oct 16;9(10):3323. | |||||
| REF 20 | E7766, a Macrocycle-Bridged Stimulator of Interferon Genes (STING) Agonist with Potent Pan-Genotypic Activity. ChemMedChem. 2021 Jun 7;16(11):1740-1743. | |||||
| REF 21 | National Cancer Institute Drug Dictionary (drug name GSK3745417). | |||||
| REF 22 | National Cancer Institute Drug Dictionary (drug name ML2118). | |||||
| REF 23 | Clinical pipeline report, company report or official report of F-star Therapeutics. | |||||
| REF 24 | Clinical pipeline report, company report or official report of Silicon Therapeutics. | |||||
| REF 25 | Immunotherapy with engineered bacteria by targeting the STING pathway for anti-tumor immunity. Nat Commun. 2020 Jun 1;11(1):2739. | |||||
| REF 26 | National Cancer Institute Drug Dictionary (drug name TAK676). | |||||
| REF 27 | Clinical pipeline report, company report or official report of GlaxoSmithKline | |||||
| REF 28 | Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage. J Neuroinflammation. 2020 May 25;17(1):165. | |||||
| REF 29 | Targeting STING with covalent small-molecule inhibitors. Nature. 2018 Jul;559(7713):269-273. | |||||
| REF 30 | Binding-pocket and lid-region substitutions render human STING sensitive to the species-specific drug DMXAA. Cell Rep. 2014 Sep 25;8(6):1668-1676. | |||||
| REF 31 | Clathrin-associated AP-1 controls termination of STING signalling. Nature. 2022 Oct;610(7933):761-767. | |||||
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