Target Information
| Target General Information | Top | |||||
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| Target ID |
T86052
(Former ID: TTDC00195)
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| Target Name |
Telomerase reverse transcriptase (TERT)
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| Synonyms |
Telomerase-associated protein 2; Telomerase catalytic subunit; TRT; TP2; TCS1; HEST2; EST2
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| Gene Name |
TERT
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Pancreatic cancer [ICD-11: 2C10] | |||||
| 2 | Human immunodeficiency virus disease [ICD-11: 1C60-1C62] | |||||
| 3 | Myelodysplastic syndrome [ICD-11: 2A37] | |||||
| Function |
Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes. Active in progenitor and cancer cells. Inactive, or very low activity, in normal somatic cells. Catalytic component of the teleromerase holoenzyme complex whose main activity is the elongation of telomeres by acting as a reverse transcriptase that adds simple sequence repeats to chromosome ends by copying a template sequence within the RNA component of the enzyme. Catalyzes the RNA-dependent extension of 3'-chromosomal termini with the 6-nucleotide telomeric repeat unit, 5'-TTAGGG-3'. The catalytic cycle involves primer binding, primer extension and release of product once the template boundary has been reached or nascent product translocation followed by further extension. More active on substrates containing 2 or 3 telomeric repeats. Telomerase activity is regulated by a number of factors including telomerase complex-associated proteins, chaperones and polypeptide modifiers. Modulates Wnt signaling. Plays important roles in aging and antiapoptosis.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.7.49
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| Sequence |
MPRAPRCRAVRSLLRSHYREVLPLATFVRRLGPQGWRLVQRGDPAAFRALVAQCLVCVPW
DARPPPAAPSFRQVSCLKELVARVLQRLCERGAKNVLAFGFALLDGARGGPPEAFTTSVR SYLPNTVTDALRGSGAWGLLLRRVGDDVLVHLLARCALFVLVAPSCAYQVCGPPLYQLGA ATQARPPPHASGPRRRLGCERAWNHSVREAGVPLGLPAPGARRRGGSASRSLPLPKRPRR GAAPEPERTPVGQGSWAHPGRTRGPSDRGFCVVSPARPAEEATSLEGALSGTRHSHPSVG RQHHAGPPSTSRPPRPWDTPCPPVYAETKHFLYSSGDKEQLRPSFLLSSLRPSLTGARRL VETIFLGSRPWMPGTPRRLPRLPQRYWQMRPLFLELLGNHAQCPYGVLLKTHCPLRAAVT PAAGVCAREKPQGSVAAPEEEDTDPRRLVQLLRQHSSPWQVYGFVRACLRRLVPPGLWGS RHNERRFLRNTKKFISLGKHAKLSLQELTWKMSVRDCAWLRRSPGVGCVPAAEHRLREEI LAKFLHWLMSVYVVELLRSFFYVTETTFQKNRLFFYRKSVWSKLQSIGIRQHLKRVQLRE LSEAEVRQHREARPALLTSRLRFIPKPDGLRPIVNMDYVVGARTFRREKRAERLTSRVKA LFSVLNYERARRPGLLGASVLGLDDIHRAWRTFVLRVRAQDPPPELYFVKVDVTGAYDTI PQDRLTEVIASIIKPQNTYCVRRYAVVQKAAHGHVRKAFKSHVSTLTDLQPYMRQFVAHL QETSPLRDAVVIEQSSSLNEASSGLFDVFLRFMCHHAVRIRGKSYVQCQGIPQGSILSTL LCSLCYGDMENKLFAGIRRDGLLLRLVDDFLLVTPHLTHAKTFLRTLVRGVPEYGCVVNL RKTVVNFPVEDEALGGTAFVQMPAHGLFPWCGLLLDTRTLEVQSDYSSYARTSIRASLTF NRGFKAGRNMRRKLFGVLRLKCHSLFLDLQVNSLQTVCTNIYKILLLQAYRFHACVLQLP FHQQVWKNPTFFLRVISDTASLCYSILKAKNAGMSLGAKGAAGPLPSEAVQWLCHQAFLL KLTRHRVTYVPLLGSLRTAQTQLSRKLPGTTLTALEAAANPALPSDFKTILD Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T78IOY | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 14 Clinical Trial Drugs | + | ||||
| 1 | GV1001 | Drug Info | Phase 3 | Pancreatic cancer | [2] | |
| 2 | Imetelstat | Drug Info | Phase 2/3 | Myelodysplastic syndrome | [3] | |
| 3 | VM1500A | Drug Info | Phase 2/3 | Human immunodeficiency virus-1 infection | [4] | |
| 4 | CB-10-01 | Drug Info | Phase 2 | Melanoma | [5] | |
| 5 | Dendritic cell vaccine | Drug Info | Phase 2 | Ovarian cancer | [6] | |
| 6 | GRNVAC1 | Drug Info | Phase 2 | Acute myeloid leukaemia | [7] | |
| 7 | Vx-001 | Drug Info | Phase 2 | Breast cancer | [8] | |
| 8 | Epithalon | Drug Info | Phase 1/2 | Ocular inflammation | [9] | |
| 9 | OBP-301 | Drug Info | Phase 1/2 | Liver cancer | [10] | |
| 10 | AAV-hTERT | Drug Info | Phase 1 | Critical limb ischemia | [11] | |
| 11 | DC/I540/KLH vaccine | Drug Info | Phase 1 | Brain cancer | [12] | |
| 12 | GRN163 | Drug Info | Phase 1 | Multiple myeloma | [13] | |
| 13 | KML-001 | Drug Info | Phase 1 | Solid tumour/cancer | [14] | |
| 14 | TeloB-Vax | Drug Info | Phase 1 | Prostate cancer | [15] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 10 Inhibitor drugs | + | ||||
| 1 | Berberine | Drug Info | [1] | |||
| 2 | Imetelstat | Drug Info | [3] | |||
| 3 | VM1500A | Drug Info | [17] | |||
| 4 | OBP-301 | Drug Info | [23] | |||
| 5 | GRN163 | Drug Info | [13] | |||
| 6 | KML-001 | Drug Info | [26] | |||
| 7 | 2,3,7-trichloro-5-nitroquinoxaline (TNQX) | Drug Info | [28] | |||
| 8 | PPA | Drug Info | [29] | |||
| 9 | Telomestatin | Drug Info | [13] | |||
| 10 | TMPyP4 | Drug Info | [13] | |||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | Epithalon | Drug Info | [22] | |||
| 2 | TeloB-Vax | Drug Info | [27] | |||
| 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: Glutathione | Ligand Info | |||||
| Structure Description | STRUCTURE OF THE HUMAN TELOMERASE THUMB DOMAIN | PDB:5UGW | ||||
| Method | X-ray diffraction | Resolution | 2.31 Å | Mutation | No | [30] |
| PDB Sequence |
KAGRNMRRKL
974 FGVLRLKCHS984 LFLDLQVNSL994 QTVCTNIYKI1004 LLLQAYRFHA1014 CVLQLPFHQQ 1024 VWKNPTFFLR1034 VISDTASLCY1044 SILKAKNAGM1054 SLGAKGAAGP1064 LPSEAVQWLC 1074 HQAFLLKLTR1084 HRVTYVPLLG1094 SLRTAQTQLS1104 RKLPGTTLTA1114 LEAAANPA |
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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).
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
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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| Degree | 25 | Degree centrality | 2.69E-03 | Betweenness centrality | 2.88E-03 |
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| Closeness centrality | 2.60E-01 | Radiality | 1.45E+01 | Clustering coefficient | 1.77E-01 |
| Neighborhood connectivity | 5.76E+01 | Topological coefficient | 6.34E-02 | Eccentricity | 11 |
| 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 Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-regulating Transcription Factors | ||||||
| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | IL2 Signaling Pathway | |||||
| PID Pathway | [+] 5 PID Pathways | + | ||||
| 1 | Validated targets of C-MYC transcriptional activation | |||||
| 2 | Regulation of Telomerase | |||||
| 3 | IL2 signaling events mediated by PI3K | |||||
| 4 | Regulation of nuclear beta catenin signaling and target gene transcription | |||||
| 5 | HIF-1-alpha transcription factor network | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Formation of the beta-catenin:TCF transactivating complex | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| Target QSAR Model | ||||||
| References | Top | |||||
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| REF 1 | Stage specificity of Plasmodium falciparum telomerase and its inhibition by berberine. Parasitol Int. 2002 Mar;51(1):99-103. | |||||
| REF 2 | ClinicalTrials.gov (NCT01579188) Study of the Telomerase Vaccine GV1001 to Treat Patients With Inoperable Stage III Non-small Cell Lung Cancer. U.S. National Institutes of Health. | |||||
| REF 3 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 4 | ClinicalTrials.gov (NCT05204394) Multicenter, Open-label, Randomized, Active Control Study to Evaluate Efficacy and Safety of Switching to VM-1500A-LAI + 2NRTIs From the 1st Line Standard of Care Therapy. U.S.National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT00925314) A Study of Transgenic Lymphocyte Immunization (TLI) Against Telomerase in Subjects With Stage III Melanoma. U.S. National Institutes of Health. | |||||
| REF 6 | Dendritic cell-targeted vaccines--hope or hype. Nat Rev Immunol. 2014 Oct;14(10):705-11. | |||||
| REF 7 | ClinicalTrials.gov (NCT00510133) A Study of Active Immunotherapy With GRNVAC1 in Patients With Acute Myelogenous Leukemia (AML). U.S. National Institutes of Health. | |||||
| REF 8 | ClinicalTrials.gov (NCT01935154) Efficacy Study of Vx001 Vaccine in NSCLC Patients. U.S. National Institutes of Health. | |||||
| 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 800021226) | |||||
| REF 10 | ClinicalTrials.gov (NCT02293850) Phase I/II Study to Evaluate the Safety and Efficacy of Telomelysin (OBP-301) in Patients With Hepatocellular Carcinoma. U.S. National Institutes of Health. | |||||
| REF 11 | ClinicalTrials.gov (NCT04110964) Evaluation of Safety and Tolerability of Libella Gene Therapy (LGT) for Critical Limb Ischemia: AAV- hTERT. U.S.National Institutes of Health. | |||||
| REF 12 | Identification of an immunogenic CD8+ T-cell epitope derived from gamma-globin, a putative tumor-associated antigen for juvenile myelomonocytic leu... Blood. 2006 Oct 15;108(8):2662-8. | |||||
| REF 13 | Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127. | |||||
| REF 14 | ClinicalTrials.gov (NCT01110226) Trial Of Cisplatin And KML-001 in Platinum Responsive Malignancies. U.S. National Institutes of Health. | |||||
| REF 15 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034068) | |||||
| REF 16 | Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: A dose escalating phase I/II study. Br J Cancer. 2006 Dec 4;95(11):1474-82. | |||||
| REF 17 | Biochemical profiling of anti-HIV prodrug Elsulfavirine (Elpida(?)) and its active form VM1500A against a panel of twelve human carbonic anhydrase isoforms. J Enzyme Inhib Med Chem. 2021 Dec;36(1):1056-1060. | |||||
| REF 18 | Telomerase immunity from bench to bedside: round one. J Transl Med. 2007 Feb 26;5:12. | |||||
| REF 19 | In vitro activation of cytotoxic T-lymphocytes by hTERT-pulsed dendritic cells. J Immunotoxicol. 2009 Dec;6(4):243-8. | |||||
| REF 20 | Targeting telomerase-expressing cancer cells. J Cell Mol Med. 2011 Jul;15(7):1433-42. | |||||
| REF 21 | Clinical pipeline report, company report or official report of Vaxon-biotech. | |||||
| REF 22 | Epithalon peptide induces telomerase activity and telomere elongation in human somatic cells. Bull Exp Biol Med. 2003 Jun;135(6):590-2. | |||||
| REF 23 | Telomerase-specific replication-selective virotherapy for human cancer. Clin Cancer Res. 2004 Jan 1;10(1 Pt 1):285-92. | |||||
| REF 24 | ClinicalTrials.gov (NCT04133649) Evaluation of Safety and Tolerability of Libella Gene Therapy (LGT) for the Treatment of Aging: AAV- hTERT. U.S.National Institutes of Health. | |||||
| REF 25 | Vaccination of cancer patients against telomerase induces functional antitumor CD8+ T lymphocytes. Clin Cancer Res. 2004 Feb 1;10(3):828-39. | |||||
| REF 26 | National Cancer Institute Drug Dictionary (drug id 672554). | |||||
| REF 27 | Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41. | |||||
| REF 28 | Identification of a quinoxaline derivative that is a potent telomerase inhibitor leading to cellular senescence of human cancer cells. Biochem J. 2003 Jul 15;373(Pt 2):523-9. | |||||
| REF 29 | Growth arrest, apoptosis, and telomere shortening of Barrett's-associated adenocarcinoma cells by a telomerase inhibitor. Gastroenterology. 2004 May;126(5):1337-46. | |||||
| REF 30 | Structural Analysis Reveals the Deleterious Effects of Telomerase Mutations in Bone Marrow Failure Syndromes. J Biol Chem. 2017 Mar 17;292(11):4593-4601. | |||||
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