Target Information
| Target General Information | Top | |||||
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| Target ID |
T51076
(Former ID: TTDI01807)
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| Target Name |
NT-3 growth factor receptor (TrkC)
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| Synonyms |
TrkC tyrosine kinase; Trk-C; TRKC; Neurotrophic tyrosine kinase receptor type 3; NT3 growth factor receptor; GP145TrkC; GP145-TrkC
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| Gene Name |
NTRK3
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Non-small-cell lung cancer [ICD-11: 2C25] | |||||
| 2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Upon binding of its ligand NTF3/neurotrophin-3, NTRK3 autophosphorylates and activates different signaling pathways, including the phosphatidylinositol 3-kinase/AKT and the MAPK pathways, that control cell survival and differentiation. Receptor tyrosine kinase involved in nervous system and probably heart development.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.10.1
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| Sequence |
MDVSLCPAKCSFWRIFLLGSVWLDYVGSVLACPANCVCSKTEINCRRPDDGNLFPLLEGQ
DSGNSNGNASINITDISRNITSIHIENWRSLHTLNAVDMELYTGLQKLTIKNSGLRSIQP RAFAKNPHLRYINLSSNRLTTLSWQLFQTLSLRELQLEQNFFNCSCDIRWMQLWQEQGEA KLNSQNLYCINADGSQLPLFRMNISQCDLPEISVSHVNLTVREGDNAVITCNGSGSPLPD VDWIVTGLQSINTHQTNLNWTNVHAINLTLVNVTSEDNGFTLTCIAENVVGMSNASVALT VYYPPRVVSLEEPELRLEHCIEFVVRGNPPPTLHWLHNGQPLRESKIIHVEYYQEGEISE GCLLFNKPTHYNNGNYTLIAKNPLGTANQTINGHFLKEPFPESTDNFILFDEVSPTPPIT VTHKPEEDTFGVSIAVGLAAFACVLLVVLFVMINKYGRRSKFGMKGPVAVISGEEDSASP LHHINHGITTPSSLDAGPDTVVIGMTRIPVIENPQYFRQGHNCHKPDTYVQHIKRRDIVL KRELGEGAFGKVFLAECYNLSPTKDKMLVAVKALKDPTLAARKDFQREAELLTNLQHEHI VKFYGVCGDGDPLIMVFEYMKHGDLNKFLRAHGPDAMILVDGQPRQAKGELGLSQMLHIA SQIASGMVYLASQHFVHRDLATRNCLVGANLLVKIGDFGMSRDVYSTDYYRLFNPSGNDF CIWCEVGGHTMLPIRWMPPESIMYRKFTTESDVWSFGVILWEIFTYGKQPWFQLSNTEVI ECITQGRVLERPRVCPKEVYDVMLGCWQREPQQRLNIKEIYKILHALGKATPIYLDILG 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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| Approved Drug(s) | [+] 2 Approved Drugs | + | ||||
| 1 | Entrectinib | Drug Info | Approved | Non-small-cell lung cancer | [2] | |
| 2 | Larotrectinib | Drug Info | Approved | Solid tumour/cancer | [3] | |
| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | MK-2461 | Drug Info | Phase 1/2 | Alzheimer disease | [4] | |
| 2 | Altiratinib | Drug Info | Phase 1 | Solid tumour/cancer | [5] | |
| Patented Agent(s) | [+] 5 Patented Agents | + | ||||
| 1 | 3-amino-5-benzyl-substituted indazole derivative 1 | Drug Info | Patented | Pruritus | [6] | |
| 2 | Azaindazole amide derivative 1 | Drug Info | Patented | Pruritus | [6] | |
| 3 | PMID28270021-Compound-WO2015042088Example4 | Drug Info | Patented | Pruritus | [6] | |
| 4 | PMID28270021-Compound-WO2016054807Example1 | Drug Info | Patented | Pruritus | [6] | |
| 5 | Pyrrolo[2,3-d]pyrimidine derivative 4 | Drug Info | Patented | Pruritus | [6] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | CEP-2563 | Drug Info | Discontinued in Phase 1 | Solid tumour/cancer | [7] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 19 Inhibitor drugs | + | ||||
| 1 | Entrectinib | Drug Info | [2] | |||
| 2 | Larotrectinib | Drug Info | [1] | |||
| 3 | MK-2461 | Drug Info | [4] | |||
| 4 | Altiratinib | Drug Info | [8] | |||
| 5 | 3-amino-5-benzyl-substituted indazole derivative 1 | Drug Info | [6] | |||
| 6 | Azaindazole amide derivative 1 | Drug Info | [6] | |||
| 7 | Cyclopenta[d]pyrimidine derivative 1 | Drug Info | [8] | |||
| 8 | PMID28270010-Compound-Figure24-b | Drug Info | [8] | |||
| 9 | PMID28270010-Compound-Figure5-1 | Drug Info | [8] | |||
| 10 | PMID28270010-Compound-Figure5-2 | Drug Info | [8] | |||
| 11 | PMID28270010-Compound-Figure5-3 | Drug Info | [8] | |||
| 12 | PMID28270021-Compound-WO2015042088Example4 | Drug Info | [6] | |||
| 13 | PMID28270021-Compound-WO2016054807Example1 | Drug Info | [6] | |||
| 14 | Pyrrolo[2,3-d]pyrimidine derivative 4 | Drug Info | [6] | |||
| 15 | AZD1332 | Drug Info | [10] | |||
| 16 | GNF-5837 | Drug Info | [11] | |||
| 17 | JNJ-28312141 | Drug Info | [12] | |||
| 18 | PMID21493067C1d | Drug Info | [13] | |||
| 19 | PMID24900538C2c | Drug Info | [14] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | CEP-2563 | Drug Info | [9] | |||
| 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: L-serine-O-phosphate | Ligand Info | |||||
| Structure Description | (R)-2-Phenylpyrrolidine Substitute Imidazopyridazines: a New Class of Potent and Selective Pan-TRK Inhibitors | PDB:4YMJ | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [15] |
| PDB Sequence |
GIHVQHIKRR
536 DIVLKRELGE546 GAFGKVFLAE556 CYNLSPTKDK566 MLVAVKALKD576 PTLAARKDFQ 586 REAELLTNLQ596 HEHIVKFYGV606 CGDGDPLIMV616 FEYMKHGDLN626 KFLRAHGPGE 650 LGLSQMLHIA660 SQIASGMVYL670 ASQHFVHRDL680 ATRNCLVGAN690 LLVKIGDFGD 703 VYTDYYRHTM731 LPIRWMPPES741 IMYRKFTTES751 DVWSFGVILW761 EIFTYGKQPW 771 FQLSNTEVIE781 CITQGRVLER791 PRVCPKEVYD801 VMLGCWQREP811 QQRLNIKEIY 821 KILHALGKAT831
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| Ligand Name: 3-[2-[6-(4-aminophenyl)imidazo[1,2-a]pyrazin-3-yl]ethynyl]-2-methyl-N-[3-(4-methylpiperazin-1-yl)-5-propan-2-ylphenyl]benzamide | Ligand Info | |||||
| Structure Description | Crystal structure of TRKc in complex with 3-((6-(4-aminophenyl)imidazo[1,2-a]pyrazin-3-yl)ethynyl)- N-(3-isopropyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)-2- methylbenzamide | PDB:6KZD | ||||
| Method | X-ray diffraction | Resolution | 1.71 Å | Mutation | No | [16] |
| PDB Sequence |
TYVQHIKRRD
537 IVLKRELGEG547 AFGKVFLAEC557 YNLSPTKDKM567 LVAVKALKDP577 TLAARKDFQR 587 EAELLTNLQH597 EHIVKFYGVC607 GDGDPLIMVF617 EYMKHGDLNK627 FLRAHGPDAG 649 ELGLSQMLHI659 ASQIASGMVY669 LASQHFVHRD679 LATRNCLVGA689 NLLVKIGDFG 699 MSRDVYSTDY709 YRLHTMLPIR735 WMPPESIMYR745 KFTTESDVWS755 FGVILWEIFT 765 YGKQPWFQLS775 NTEVIECITQ785 GRVLERPRVC795 PKEVYDVMLG805 CWQREPQQRL 815 NIKEIYKILH825 ALGKATPIYL835 DI
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LEU544
4.111
VAL552
3.895
ALA570
3.178
LYS572
3.561
GLU588
2.650
LEU591
3.684
LEU592
3.627
LEU595
3.526
ILE600
4.444
VAL601
3.633
PHE617
3.730
GLU618
2.914
TYR619
3.509
MET620
2.856
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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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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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| Calcium signaling pathway | hsa04020 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Neurotrophin signaling pathway | hsa04722 | Affiliated Target |
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| Class: Organismal Systems => Nervous system | Pathway Hierarchy | ||
| Degree | 10 | Degree centrality | 1.07E-03 | Betweenness centrality | 3.71E-04 |
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| Closeness centrality | 2.26E-01 | Radiality | 1.40E+01 | Clustering coefficient | 2.67E-01 |
| Neighborhood connectivity | 3.68E+01 | Topological coefficient | 1.57E-01 | Eccentricity | 12 |
| 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 Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Drug Resistance Mutation (DRM) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| Reactome | [+] 3 Reactome Pathways | + | ||||
| 1 | ARMS-mediated activation | |||||
| 2 | NGF-independant TRKA activation | |||||
| 3 | PI3K/AKT activation | |||||
| WikiPathways | [+] 4 WikiPathways | + | ||||
| 1 | MAPK Signaling Pathway | |||||
| 2 | BDNF signaling pathway | |||||
| 3 | Integrated Pancreatic Cancer Pathway | |||||
| 4 | NGF signalling via TRKA from the plasma membrane | |||||
| References | Top | |||||
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| REF 1 | 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89. | |||||
| REF 2 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019 | |||||
| REF 3 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 4 | MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33. | |||||
| 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 800040094) | |||||
| REF 6 | Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Part II.Expert Opin Ther Pat. 2017 Jul;27(7):831-849. | |||||
| REF 7 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007988) | |||||
| REF 8 | Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Part I.Expert Opin Ther Pat. 2017 Jun;27(6):733-751. | |||||
| REF 9 | Phase I clinical trial of CEP-2563 dihydrochloride, a receptor tyrosine kinase inhibitor, in patients with refractory solid tumors. Invest New Drugs. 2004 Nov;22(4):449-58. | |||||
| REF 10 | 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: 1817). | |||||
| REF 11 | Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models. ACS Med Chem Lett. 2012 Jan 1;3(2):140-5. | |||||
| REF 12 | JNJ-28312141, a novel orally active colony-stimulating factor-1 receptor/FMS-related receptor tyrosine kinase-3 receptor tyrosine kinase inhibitor with potential utility in solid tumors, bone metastases, and acute myeloid leukemia. Mol Cancer Ther. 2009 Nov;8(11):3151-61. | |||||
| REF 13 | In vitro and in vivo evaluation of 6-aminopyrazolyl-pyridine-3-carbonitriles as JAK2 kinase inhibitors. Bioorg Med Chem Lett. 2011 May 15;21(10):2958-61. | |||||
| REF 14 | Discovery of Disubstituted Imidazo[4,5-b]pyridines and Purines as Potent TrkA Inhibitors. ACS Med Chem Lett. 2012 Jul 26;3(9):705-9. | |||||
| REF 15 | (R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors. ACS Med Chem Lett. 2015 Mar 16;6(5):562-7. | |||||
| REF 16 | Design, synthesis and biological evaluation of 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-methylbenzamides as potent and selective pan-tropomyosin receptor kinase (TRK) inhibitors. Eur J Med Chem. 2019 Oct 1;179:470-482. | |||||
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