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neurotrophic receptor tyrosine kinase 2

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Target id: 1818

Nomenclature: neurotrophic receptor tyrosine kinase 2

Abbreviated Name: trkB

Family: Type VII RTKs: Neurotrophin receptor/Trk family

Contents:

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) | neurotrophic tyrosine kinase | neurotrophic tyrosine kinase, receptor, type 2 | neurotrophic tyrosine kinase receptor type 2 | TRKB1
Database Links Click here for help
Alphafold Q16620 (Hs), P15209 (Mm), Q63604 (Rn)
BRENDA 2.7.10.1
CATH/Gene3D 2.60.40.10, 3.80.10.10
ChEMBL Target CHEMBL4898 (Hs), CHEMBL4523190 (Mm), CHEMBL1795111 (Rn)
Ensembl Gene ENSG00000148053 (Hs), ENSMUSG00000055254 (Mm), ENSRNOG00000018839 (Rn)
Entrez Gene 4915 (Hs), 18212 (Mm), 25054 (Rn)
Human Protein Atlas ENSG00000148053 (Hs)
KEGG Enzyme 2.7.10.1
KEGG Gene hsa:4915 (Hs), mmu:18212 (Mm), rno:25054 (Rn)
OMIM 600456 (Hs)
Orphanet ORPHA363263 (Hs)
Pharos Q16620 (Hs)
RefSeq Nucleotide NM_001007097 (Hs), NM_001025074 (Mm), NM_001163168 (Rn)
RefSeq Protein NP_001007098 (Hs), NP_001020245 (Mm), NP_032771 (Mm), NP_036863 (Rn)
SynPHARM 83183 (in complex with GW-2580)
UniProtKB Q16620 (Hs), P15209 (Mm), Q63604 (Rn)
Wikipedia NTRK2 (Hs)
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:  20
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 21
⤷ pKd 8.0 (Kd 1.1x10-8 M) [21]
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 13
⤷ pIC50 10.0 (IC50 1x10-10 M) [13]
Description: In a biochemical assay measuring inhibition of peptide substrate phosphorylation by the test compound in the presence ot recombinant human TrkB.
zurletrectinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.8 pIC50 19
⤷ pIC50 9.8 (IC50 1.45x10-10 M) [19]
repotrectinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.5 pIC50 6
⤷ pIC50 9.5 (IC50 3x10-10 M) IC50 for TRKBG639R is 2.7 nM [6]
emzeltrectinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition >9.0 pIC50 16
⤷ pIC50 >9.0 (IC50 <1x10-9 M) [16]
CH7057288 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.7 pIC50 11
⤷ pIC50 8.7 (IC50 2x10-9 M) [11]
taletrectinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.6 pIC50 14
⤷ pIC50 8.6 (IC50 2.28x10-9 M) [14]
selitrectinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.5 pIC50 17
⤷ pIC50 8.5 (IC50 3.2x10-9 M) [17]
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 15
⤷ pIC50 8.1 (IC50 8x10-9 M) [15]
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 18
⤷ pIC50 7.2 (IC50 6.1x10-8 M) [18]
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: 5,22
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 Ligand has a PDB structure 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 Immunopharmacology Ligand 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
Immuno Process:  Inflammation
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:  12

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. Ito T, Kinoshita K, Tomizawa M, Shinohara S, Nishii H, Matsushita M, Hattori K, Kohchi Y, Kohchi M, Hayase T et al.. (2022) Discovery of CH7057288 as an Orally Bioavailable, Selective, and Potent pan-TRK Inhibitor. J Med Chem, 65 (18): 12427-12444. [PMID:36066182]

12. 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]

13. 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.

14. 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]

15. 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]

16. Li Z, Hu Y, Wei W, Liguang D, Xiaowei D, Yanqing Y, Yinghui S, Yongxin H, Yong P, Fansheng K. (2018) Amino pyrazolopyrimidine compound used as neurotrophic factor tyrosine kinase receptor inhibitor. Patent number: WO2018077246A1. Assignee: Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Beijing Sailintai Pharmaceutical Technology Co., Ltd., Lianyungang Runzhong Pharmaceutical Co., Ltd.. Priority date: 27/10/2017. Publication date: 03/05/2018.

17. 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.

18. 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]

19. Roa P, Foglizzo V, Harada G, Repetto M, Kulick A, de Stanchina E, de Marchena M, Auwardt S, Sayed Ahmed S, Bremer NV et al.. (2024) Zurletrectinib is a next-generation TRK inhibitor with strong intracranial activity against NTRK fusion-positive tumours with on-target resistance to first-generation agents. Br J Cancer, 131 (3): 601-610. [PMID:38902532]

20. 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]

21. 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]

22. 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 18/07/2024. Accessed on 12/10/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1818.