Target Information
Target General Information | Top | |||||
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Target ID |
T84703
(Former ID: TTDNR00649)
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Target Name |
BDNF/NT-3 growth factors receptor (TrkB)
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Synonyms |
Tropomyosin-related kinase B; TrkB tyrosine kinase; Trk-B; TRKB; Neurotrophic tyrosine kinase receptor type 2; GP145-TrkB
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Gene Name |
NTRK2
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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 |
Receptor for BDNF/brain-derived neurotrophic factor and NTF4/neurotrophin-4. Alternatively can also bind NTF3/neurotrophin-3 which is less efficient in activating the receptor but regulates neuron survival through NTRK2. Upon ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades. Through SHC1, FRS2, SH2B1, SH2B2 activates the GRB2-Ras-MAPK cascade that regulates for instance neuronal differentiation including neurite outgrowth. Through the same effectors controls the Ras-PI3 kinase-AKT1 signaling cascade that mainly regulates growth and survival. Through PLCG1 and the downstream protein kinase C-regulated pathways controls synaptic plasticity. Thereby, plays a role in learning and memory by regulating both short term synaptic function and long-term potentiation. PLCG1 also leads to NF-Kappa-B activation and the transcription of genes involved in cell survival. Hence, it is able to suppress anoikis, the apoptosis resulting from loss of cell-matrix interactions. May also play a role in neutrophin-dependent calcium signaling in glial cells and mediate communication between neurons and glia. Receptor tyrosine kinase involved in the development and the maturation of the central and the peripheral nervous systems through regulation of neuron survival, proliferation, migration, differentiation, and synapse formation and plasticity.
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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 |
MSSWIRWHGPAMARLWGFCWLVVGFWRAAFACPTSCKCSASRIWCSDPSPGIVAFPRLEP
NSVDPENITEIFIANQKRLEIINEDDVEAYVGLRNLTIVDSGLKFVAHKAFLKNSNLQHI NFTRNKLTSLSRKHFRHLDLSELILVGNPFTCSCDIMWIKTLQEAKSSPDTQDLYCLNES SKNIPLANLQIPNCGLPSANLAAPNLTVEEGKSITLSCSVAGDPVPNMYWDVGNLVSKHM NETSHTQGSLRITNISSDDSGKQISCVAENLVGEDQDSVNLTVHFAPTITFLESPTSDHH WCIPFTVKGNPKPALQWFYNGAILNESKYICTKIHVTNHTEYHGCLQLDNPTHMNNGDYT LIAKNEYGKDEKQISAHFMGWPGIDDGANPNYPDVIYEDYGTAANDIGDTTNRSNEIPST DVTDKTGREHLSVYAVVVIASVVGFCLLVMLFLLKLARHSKFGMKGPASVISNDDDSASP LHHISNGSNTPSSSEGGPDAVIIGMTKIPVIENPQYFGITNSQLKPDTFVQHIKRHNIVL KRELGEGAFGKVFLAECYNLCPEQDKILVAVKTLKDASDNARKDFHREAELLTNLQHEHI VKFYGVCVEGDPLIMVFEYMKHGDLNKFLRAHGPDAVLMAEGNPPTELTQSQMLHIAQQI AAGMVYLASQHFVHRDLATRNCLVGENLLVKIGDFGMSRDVYSTDYYRVGGHTMLPIRWM PPESIMYRKFTTESDVWSLGVVLWEIFTYGKQPWYQLSNNEVIECITQGRVLQRPRTCPQ EVYELMLGCWQREPHMRKNIKGIHTLLQNLAKASPVYLDILG Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
HIT2.0 ID | T07S0E |
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) | [+] 1 Clinical Trial Drugs | + | ||||
1 | MK-2461 | Drug Info | Phase 1/2 | Alzheimer disease | [4] | |
Patented Agent(s) | [+] 6 Patented Agents | + | ||||
1 | 3-amino-5-benzyl-substituted indazole derivative 1 | Drug Info | Patented | Pruritus | [5] | |
2 | Azaindazole amide derivative 1 | Drug Info | Patented | Pruritus | [5] | |
3 | Macrocycle derivative 13 | Drug Info | Patented | Cell proliferative disorder | [6] | |
4 | PMID28270021-Compound-WO2015042088Example4 | Drug Info | Patented | Pruritus | [5] | |
5 | PMID28270021-Compound-WO2016054807Example1 | Drug Info | Patented | Pruritus | [5] | |
6 | Pyrrolo[2,3-d]pyrimidine derivative 4 | Drug Info | Patented | Pruritus | [5] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Inhibitor | [+] 17 Inhibitor drugs | + | ||||
1 | Entrectinib | Drug Info | [2] | |||
2 | Larotrectinib | Drug Info | [1] | |||
3 | MK-2461 | Drug Info | [4] | |||
4 | 3-amino-5-benzyl-substituted indazole derivative 1 | Drug Info | [5] | |||
5 | Azaindazole amide derivative 1 | Drug Info | [5] | |||
6 | Cyclopenta[d]pyrimidine derivative 1 | Drug Info | [6] | |||
7 | Macrocycle derivative 13 | Drug Info | [6] | |||
8 | PMID28270010-Compound-Figure24-b | Drug Info | [6] | |||
9 | PMID28270010-Compound-Figure5-1 | Drug Info | [6] | |||
10 | PMID28270010-Compound-Figure5-2 | Drug Info | [6] | |||
11 | PMID28270010-Compound-Figure5-3 | Drug Info | [6] | |||
12 | PMID28270021-Compound-WO2015042088Example4 | Drug Info | [5] | |||
13 | PMID28270021-Compound-WO2016054807Example1 | Drug Info | [5] | |||
14 | Pyrrolo[2,3-d]pyrimidine derivative 4 | Drug Info | [5] | |||
15 | AZD1332 | Drug Info | [7] | |||
16 | GNF-5837 | Drug Info | [8] | |||
17 | PMID24432909C8e | Drug Info | [9] | |||
Modulator | [+] 1 Modulator drugs | + | ||||
1 | TrkB NAM | Drug Info | [7] |
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-interacting Proteins |
Target Profiles in Patients | Top | |||||
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Target Expression Profile (TEP) |
Target Affiliated Biological Pathways | Top | |||||
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KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
1 | MAPK signaling pathway | |||||
2 | Neurotrophin signaling pathway | |||||
3 | Alcoholism | |||||
PID Pathway | [+] 3 PID Pathways | + | ||||
1 | SHP2 signaling | |||||
2 | Posttranslational regulation of adherens junction stability and dissassembly | |||||
3 | Neurotrophic factor-mediated Trk receptor signaling | |||||
Reactome | [+] 1 Reactome Pathways | + | ||||
1 | NGF-independant TRKA activation | |||||
WikiPathways | [+] 2 WikiPathways | + | ||||
1 | SIDS Susceptibility Pathways | |||||
2 | BDNF signaling pathway |
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 | Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Part II.Expert Opin Ther Pat. 2017 Jul;27(7):831-849. | |||||
REF 6 | Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Part I.Expert Opin Ther Pat. 2017 Jun;27(6):733-751. | |||||
REF 7 | 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: 1818). | |||||
REF 8 | 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 9 | Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib. J Med Chem.> 2014 Feb 27;57(4):1170-87. |
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