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neurotrophic receptor tyrosine kinase 2

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Target not currently curated in GtoImmuPdb

Target id: 1818

Nomenclature: neurotrophic receptor tyrosine kinase 2

Abbreviated Name: trkB

Family: Type VII RTKs: Neurotrophin receptor/Trk family

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 822 9q21.33 NTRK2 neurotrophic receptor tyrosine kinase 2
Mouse 1 821 13 31.2 cM Ntrk2 neurotrophic tyrosine kinase, receptor, type 2
Rat 1 821 17p14 Ntrk2 neurotrophic receptor tyrosine kinase 2
Previous and Unofficial Names Click here for help
BDNF/NT-3 growth factors receptor | Neural receptor protein-tyrosine kinase (trkB) | TRKB1 | neurotrophic tyrosine kinase, receptor, type 2 | neurotrophic tyrosine kinase receptor type 2 | neurotrophic tyrosine kinase
Database Links Click here for help
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
Pharos
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  The crystal structures of TrkA and TrkB suggest key regions for achieving selective inhibition.
PDB Id:  4ASZ
Resolution:  1.7Å
Species:  Human
References:  4
Image of receptor 3D structure from RCSB PDB
Description:  Ligand binding domain of human TRKB receptor.
PDB Id:  1WWB
Resolution:  2.1Å
Species:  Human
References:  17
Enzyme Reaction Click here for help
EC Number: 2.7.10.1
Endogenous ligands (Human)
BDNF (BDNF, P23560), neurotrophin-4 (NTF4, P34130) > neurotrophin-3 (NTF3, P20783)

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
DDR1/2 inhibitor 5n Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.0 pKd 18
pKd 8.0 (Kd 1.1x10-8 M) [18]
GW-2580 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.4 pKd 5
pKd 7.4 (Kd 3.6x10-8 M) [5]
GR-389988 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 10.0 pIC50 12
pIC50 10.0 (IC50 1x10-10 M) [12]
Description: In a biochemical assay measuring inhibition of peptide substrate phosphorylation by the test compound in the presence ot recombinant human TrkB.
repotrectinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.5 pIC50 6
pIC50 9.5 (IC50 3x10-10 M) IC50 for TRKBG639R is 2.7 nM [6]
DS-6051b Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.6 pIC50 13
pIC50 8.6 (IC50 2.28x10-9 M) [13]
selitrectinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.5 pIC50 15
pIC50 8.5 (IC50 3.2x10-9 M) [15]
compound 8e [PMID: 24432909] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.4 pIC50 8
pIC50 8.4 (IC50 4x10-9 M) [8]
AZD1332 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition >8.3 pIC50 3
pIC50 >8.3 (IC50 <5x10-9 M) [3]
Description: NIH3T3 cells over expressing TrkB
CEP-11981 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.3 pIC50 9
pIC50 8.3 (IC50 5x10-9 M) [9]
RIPK1 inhibitor 22b Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.1 pIC50 14
pIC50 8.1 (IC50 8x10-9 M) [14]
GNF-5837 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.1 pIC50 1
pIC50 8.1 (IC50 9x10-9 M) [1]
MK-2461 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.2 pIC50 16
pIC50 7.2 (IC50 6.1x10-8 M) [16]
ONO-7579 Small molecule or natural product N/A Inhibition - - 10
[10]
View species-specific inhibitor tables
DiscoveRx KINOMEscan® screen Click here for help
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 5,19

Key to terms and symbols Click column headers to sort
Target used in screen: TRKB
Ligand Sp. Type Action Value Parameter
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.4 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.4 pKd
lestaurtinib Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 7.8 pKd
GW-2580 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.4 pKd
crizotinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.4 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 6.9 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.9 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.8 pKd
AST-487 Small molecule or natural product Hs Inhibitor Inhibition 6.7 pKd
tozasertib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.6 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx


Reference: 2,7

Key to terms and symbols Click column headers to sort
Target used in screen: TrkB/TRKB
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 0.4 14.5 -6.0
Gö 6976 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 0.8 44.0 -12.0
indirubin derivative E804 Small molecule or natural product Hs Inhibitor Inhibition 1.6 -2.0 0.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 2.1 0.0 0.0
aminopurvalanol A Small molecule or natural product Hs Inhibitor Inhibition 3.0 10.0 1.0
indirubin-3'-monoxime Small molecule or natural product Hs Inhibitor Inhibition 4.1 0.0 0.0
GSK-3 inhibitor XIII Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 4.4 1.0 0.0
Syk inhibitor Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 4.8 23.0 -12.0
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 5.7
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 6.9 19.0 14.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immuno Process Associations
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 1 GO processes
GO:0071356 cellular response to tumor necrosis factor IEP
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes
GO:0006954 inflammatory response IEP
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Obesity, hyperphagia, and developmental delay; OBHD
OMIM: 613886
Disease:  Pilocytic astrocytoma
Disease Ontology: DOID:4851
Orphanet: ORPHA251612
References:  11

References

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1. Albaugh P, Fan Y, Mi Y, Sun F, Adrian F, Li N, Jia Y, Sarkisova Y, Kreusch A, Hood T et al.. (2012) Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models. ACS Med Chem Lett, 3 (2): 140-5. [PMID:24900443]

2. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1039-45. [PMID:22037377]

3. AstraZeneca. AZD1332. Accessed on 11/09/2014. Modified on 11/09/2014. AstraZeneca.com, http://openinnovation.astrazeneca.com/what-we-offer/compound/azd1332/

4. Bertrand T, Kothe M, Liu J, Dupuy A, Rak A, Berne PF, Davis S, Gladysheva T, Valtre C, Crenne JY et al.. (2012) The crystal structures of TrkA and TrkB suggest key regions for achieving selective inhibition. J. Mol. Biol., 423 (3): 439-53. [PMID:22902478]

5. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1046-51. [PMID:22037378]

6. Drilon A, Ou SI, Cho BC, Kim DW, Lee J, Lin JJ, Zhu VW, Ahn MJ, Camidge DR, Nguyen J et al.. (2018) Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations. Cancer Discov, 8 (10): 1227-1236. [PMID:30093503]

7. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem. J., 451 (2): 313-28. [PMID:23398362]

8. Huang Q, Johnson TW, Bailey S, Brooun A, Bunker KD, Burke BJ, Collins MR, Cook AS, Cui JJ, Dack KN et al.. (2014) Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib. J. Med. Chem., 57 (4): 1170-87. [PMID:24432909]

9. Hudkins RL, Becknell NC, Zulli AL, Underiner TL, Angeles TS, Aimone LD, Albom MS, Chang H, Miknyoczki SJ, Hunter K et al.. (2012) Synthesis and biological profile of the pan-vascular endothelial growth factor receptor/tyrosine kinase with immunoglobulin and epidermal growth factor-like homology domains 2 (VEGF-R/TIE-2) inhibitor 11-(2-methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (CEP-11981): a novel oncology therapeutic agent. J. Med. Chem., 55 (2): 903-13. [PMID:22148921]

10. Iida H, Fujikawa R, Kozaki R, Harada R, Hosokawa Y, Ogawara KI, Ohno T. (2020) Pharmacokinetic-Pharmacodynamic-Efficacy Modeling of ONO-7579, a Novel Pan-Tropomyosin Receptor Kinase Inhibitor, in a Murine Xenograft Tumor Model. J. Pharmacol. Exp. Ther., 373 (3): 361-369. [PMID:32217770]

11. Jones DT, Hutter B, Jäger N, Korshunov A, Kool M, Warnatz HJ, Zichner T, Lambert SR, Ryzhova M, Quang DA et al.. (2013) Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat. Genet., 45 (8): 927-32. [PMID:23817572]

12. Kane JL Jr, Matthews G, Metz M, Kothe M, Liu J, Scholte A. (2015) Tropomyosin-related kinase (Trk) inhibitors. Patent number: US9174986B2. Assignee: Genzyme Corp.. Priority date: 10/12/2013. Publication date: 03/11/2015.

13. Katayama R, Gong B, Togashi N, Miyamoto M, Kiga M, Iwasaki S, Kamai Y, Tominaga Y, Takeda Y, Kagoshima Y et al.. (2019) The new-generation selective ROS1/NTRK inhibitor DS-6051b overcomes crizotinib resistant ROS1-G2032R mutation in preclinical models. Nat Commun, 10 (1): 3604. [PMID:31399568]

14. Li Y, Xiong Y, Zhang G, Zhang L, Yang W, Yang J, Huang L, Qiao Z, Miao Z, Lin G et al.. (2018) Identification of 5-(2,3-Dihydro-1 H-indol-5-yl)-7 H-pyrrolo[2,3- d]pyrimidin-4-amine Derivatives as a New Class of Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors, Which Showed Potent Activity in a Tumor Metastasis Model. J. Med. Chem., 61 (24): 11398-11414. [PMID:30480444]

15. Nanda N, Bilenker JH, Doebele RC, Blake JF, Kolakowski GR, Brandhuber BJ, Andrews SW. (2017) Point mutations in trk inhibitor-resistant cancer and methods relating to the same. Patent number: WO2017075107A1. Assignee: Array Biopharma Inc, Loxo Oncology Inc. Priority date: 26/10/2015. Publication date: 04/05/2017.

16. Pan BS, Chan GK, Chenard M, Chi A, Davis LJ, Deshmukh SV, Gibbs JB, Gil S, Hang G, Hatch H et al.. (2010) MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res., 70 (4): 1524-33. [PMID:20145145]

17. Ultsch MH, Wiesmann C, Simmons LC, Henrich J, Yang M, Reilly D, Bass SH, de Vos AM. (1999) Crystal structures of the neurotrophin-binding domain of TrkA, TrkB and TrkC. J. Mol. Biol., 290 (1): 149-59. [PMID:10388563]

18. Wang Z, Zhang Y, Pinkas DM, Fox AE, Luo J, Huang H, Cui S, Xiang Q, Xu T, Xun Q et al.. (2018) Design, Synthesis, and Biological Evaluation of 3-(Imidazo[1,2- a]pyrazin-3-ylethynyl)-4-isopropyl- N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide as a Dual Inhibitor of Discoidin Domain Receptors 1 and 2. J. Med. Chem., 61 (17): 7977-7990. [PMID:30075624]

19. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem. Biol., 17 (11): 1241-9. [PMID:21095574]

How to cite this page

Type VII RTKs: Neurotrophin receptor/Trk family: neurotrophic receptor tyrosine kinase 2. Last modified on 21/08/2020. Accessed on 02/12/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1818.