Target Information
| Target General Information | Top | |||||
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| Target ID |
T76233
(Former ID: TTDNR00686)
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| Target Name |
Hepatitis A virus cellular receptor 2 (TIM3)
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| Synonyms |
TIMD3; TIMD-3; TIM3; TIM-3; T-cell membrane protein 3; T-cell immunoglobulin mucin receptor 3; T-cell immunoglobulin and mucin domain-containing protein 3; HAVcr-2; HAVCR2; CD366
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| Gene Name |
Hepatitis A virus HAVCR2
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Myelodysplastic syndrome [ICD-11: 2A37] | |||||
| Function |
Generally accepted to have an inhibiting function. Reports on stimulating functions suggest that the activity may be influenced by the cellular context and/or the respective ligand. Regulates macrophage activation. Inhibits T-helper type 1 lymphocyte (Th1)-mediated auto- and alloimmune responses and promotes immunological tolerance. In CD8+ cells attenuates TCR-induced signaling, specifically by blocking NF-kappaB and NFAT promoter activities resulting in the loss of IL-2 secretion. The function may implicate its association with LCK proposed to impair phosphorylation of TCR subunits, and/or LGALS9-dependent recruitment of PTPRC to the immunological synapse. In contrast, shown to activate TCR-induced signaling in T-cells probably implicating ZAP70, LCP2, LCK and FYN. Expressed on Treg cells can inhibit Th17 cell responses. Receptor for LGALS9. Binding to LGALS9 is believed to result in suppression of T-cell responses; the resulting apoptosis of antigen-specific cells may implicate HAVCR2 phosphorylation and disruption of its association with BAG6. Binding to LGALS9 is proposed to be involved in innate immune response to intracellular pathogens. Expressed on Th1 cells interacts with LGALS9 expressed on Mycobacterium tuberculosis-infected macrophages to stimulate antibactericidal activity including IL-1 beta secretion and to restrict intracellular bacterial growth. However, the function as receptor for LGALS9 has been challenged. Also reported to enhance CD8+ T-cell responses to an acute infection such as by Listeria monocytogenes. Receptor for phosphatidylserine (PtSer); PtSer-binding is calcium-dependent. May recognize PtSer on apoptotic cells leading to their phagocytosis. Mediates the engulfment of apoptotic cells by dendritic cells. Expressed on T-cells, promotes conjugation but not engulfment of apoptotic cells. Expressed on dendritic cells (DCs) positively regulates innate immune response and in synergy with Toll-like receptors promotes secretion of TNF-alpha. In tumor-imfiltrating DCs suppresses nucleic acid-mediated innate immune repsonse by interaction with HMGB1 and interfering with nucleic acid-sensing and trafficking of nucleid acids to endosomes. Expressed on natural killer (NK) cells acts as a coreceptor to enhance IFN-gamma production in response to LGALS9. In contrast, shown to suppress NK cell-mediated cytotoxicity. Negatively regulates NK cell function in LPS-induced endotoxic shock. Cell surface receptor implicated in modulating innate and adaptive immune responses.
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| BioChemical Class |
Immunoglobulin
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| UniProt ID | ||||||
| Sequence |
MFSHLPFDCVLLLLLLLLTRSSEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPV
FECGNVVLRTDERDVNYWTSRYWLNGDFRKGDVSLTIENVTLADSGIYCCRIQIPGIMND EKFNLKLVIKPAKVTPAPTRQRDFTAAFPRMLTTRGHGPAETQTLGSLPDINLTQISTLA NELRDSRLANDLRDSGATIRIGIYIGAGICAGLALALIFGALIFKWYSHSKEKIQNLSLI SLANLPPSGLANAVAEGIRSEENIYTIEENVYEVEEPNEYYCYVSSRQQPSQPLGCRFAM P 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) | [+] 10 Clinical Trial Drugs | + | ||||
| 1 | MBG453 | Drug Info | Phase 3 | Myelodysplastic syndrome | [2] | |
| 2 | AZD7789 | Drug Info | Phase 2 | Hodgkin lymphoma | [3] | |
| 3 | GSK4069889 | Drug Info | Phase 2 | Non-small-cell lung cancer | [4] | |
| 4 | RO7121661 | Drug Info | Phase 2 | Esophageal squamous cell carcinoma | [5] | |
| 5 | TB006 | Drug Info | Phase 2 | Alzheimer disease | [6] | |
| 6 | BGB-A425 | Drug Info | Phase 1/2 | Solid tumour/cancer | [7] | |
| 7 | INCAGN2390 | Drug Info | Phase 1 | Solid tumour/cancer | [8] | |
| 8 | LY3321367 | Drug Info | Phase 1 | Solid tumour/cancer | [1] | |
| 9 | LY3415244 | Drug Info | Phase 1 | Solid tumour/cancer | [9] | |
| 10 | Sym023 | Drug Info | Phase 1 | Lymphoma | [10] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 5 Inhibitor drugs | + | ||||
| 1 | GSK4069889 | Drug Info | [12] | |||
| 2 | RO7121661 | Drug Info | [13] | |||
| 3 | INCAGN2390 | Drug Info | [16] | |||
| 4 | LY3415244 | Drug Info | [17] | |||
| 5 | Sym023 | Drug Info | [18] | |||
| 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: N-{4-[(4S,10aP)-8-chloro-2-methyl-5-oxo-5,6-dihydro[1,2,4]triazolo[1,5-c]quinazolin-9-yl]-3-methylphenyl}methanesulfonamide | Ligand Info | |||||
| Structure Description | Structure of TIM-3 in complex with N-(4-(8-chloro-2-mehtyl-5-oxo-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-9-yl)-3-methylphenyl)methanesulfonamdide (compound 35) | PDB:7M3Z | ||||
| Method | X-ray diffraction | Resolution | 1.40 Å | Mutation | No | [19] |
| PDB Sequence |
SEVEYRAEVG
10 QNAYLPCFYT20 PAAPGNLVPV30 CWGKGACPVF40 ECGNVVLRTD50 ERDVNYWTSR 60 YWLNGDFRKG70 DVSLTIENVT80 LADSGIYCCR90 IQIPGIMNDE100 KFNLKLVIK |
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| Ligand Name: (4R,10aP)-8-chloro-2-methyl-9-(3-methylpyridin-4-yl)[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one | Ligand Info | |||||
| Structure Description | Structure of TIM-3 in complex with 8-chloro-2-methyl-9-(3-mehtylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one (compound 22) | PDB:7M3Y | ||||
| Method | X-ray diffraction | Resolution | 1.69 Å | Mutation | No | [19] |
| PDB Sequence |
SEVEYRAEVG
10 QNAYLPCFYT20 PAAPGNLVPV30 CWGKGACPVF40 ECGNVVLRTD50 ERDVNYWTSR 60 YWLNGDFRKG70 DVSLTIENVT80 LADSGIYCCR90 IQIPGIMNDE100 KFNLKLVIK |
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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).
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
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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| Degree | 5 | Degree centrality | 5.37E-04 | Betweenness centrality | 1.62E-04 |
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| Closeness centrality | 2.18E-01 | Radiality | 1.38E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 2.40E+01 | Topological coefficient | 2.04E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| References | Top | |||||
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| REF 1 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 2 | ClinicalTrials.gov (NCT04266301) Study of Efficacy and Safety of MBG453 in Combination With Azacitidine in Subjects With Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS) as Per IPSS-R, or Chronic Myelomonocytic Leukemia-2 (CMML-2) (STIMULUS-MDS2). U.S. National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT05216835) A Phase I/II Open-label, Multi-center Study to Assess Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of AZD7789, an Anti-PD-1 and Anti-TIM-3 Bispecific Antibody, in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma. U.S.National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT04655976) Study of Cobolimab in Combination With Dostarlimab and Docetaxel in Advanced NSCLC Participants (COSTAR Lung). U.S. National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT04785820) A Study of RO7121661 and RO7247669 Compared With Nivolumab in Participants With Advanced or Metastatic Squamous Cell Carcinoma of the Esophagus. U.S. National Institutes of Health. | |||||
| REF 6 | ClinicalTrials.gov (NCT05476783) A Multi-center Open-label Long Term Extension Study to Assess the Safety of TB006 in Patients Who Have Completed Protocol TB006AD2102 and in De Novo Patients With Alzheimer's Disease. U.S.National Institutes of Health. | |||||
| REF 7 | ClinicalTrials.gov (NCT03744468) Study of BGB-A425 in Combination With Tislelizumab in Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 8 | ClinicalTrials.gov (NCT03652077) A Safety and Tolerability Study of INCAGN02390 in Select Advanced Malignancies. U.S. National Institutes of Health. | |||||
| REF 9 | ClinicalTrials.gov (NCT03752177) A Study of LY3415244 in Participants With Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 10 | ClinicalTrials.gov (NCT03489343) Sym023 (Anti-TIM-3) in Patients With Advanced Solid Tumor Malignancies or Lymphomas. U.S. National Institutes of Health. | |||||
| REF 11 | Clinical pipeline report, company report or official report of AstraZeneca | |||||
| REF 12 | Clinical pipeline report, company report or official report of GlaxoSmithKline. | |||||
| REF 13 | Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 2019 Aug;18(8):585-608. | |||||
| REF 14 | Clinical pipeline report, company report or official report of TrueBinding | |||||
| REF 15 | Clinical pipeline report, company report or official report of BeiGene. | |||||
| REF 16 | Clinical pipeline report, company report or official report of Agenus. | |||||
| REF 17 | Safety and Immunogenicity of LY3415244, a Bispecific Antibody Against TIM-3 and PD-L1, in Patients With Advanced Solid Tumors. Clin Cancer Res. 2021 May 15;27(10):2773-2781. | |||||
| REF 18 | Clinical pipeline report, company report or official report of Symphogen. | |||||
| REF 19 | Fragment-Based Discovery of Small Molecules Bound to T-Cell Immunoglobulin and Mucin Domain-Containing Molecule 3 (TIM-3). J Med Chem. 2021 Oct 14;64(19):14757-14772. | |||||
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