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neurotrophic receptor tyrosine kinase 3

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Target id: 1819

Nomenclature: neurotrophic receptor tyrosine kinase 3

Abbreviated Name: trkC

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 1 839 15q25.3 NTRK3 neurotrophic receptor tyrosine kinase 3
Mouse 1 825 7 44.01 cM Ntrk3 neurotrophic tyrosine kinase, receptor, type 3
Rat 1 864 1q31 Ntrk3 neurotrophic receptor tyrosine kinase 3
Previous and Unofficial Names Click here for help
GP145-TrkC | NT-3 growth factor receptor | neural receptor protein-tyrosine kinase (trkC) | neurotrophic tyrosine kinase
Database Links Click here for help
Alphafold Q16288 (Hs), Q6VNS1 (Mm), Q03351 (Rn)
BRENDA 2.7.10.1
CATH/Gene3D 3.80.10.10, 2.60.40.10
ChEMBL Target CHEMBL5608 (Hs), CHEMBL2791 (Mm)
Ensembl Gene ENSG00000140538 (Hs), ENSMUSG00000059146 (Mm), ENSRNOG00000018674 (Rn)
Entrez Gene 4916 (Hs), 18213 (Mm), 29613 (Rn)
Human Protein Atlas ENSG00000140538 (Hs)
KEGG Enzyme 2.7.10.1
KEGG Gene hsa:4916 (Hs), mmu:18213 (Mm), rno:29613 (Rn)
OMIM 191316 (Hs)
Orphanet ORPHA246681 (Hs)
Pharos Q16288 (Hs)
RefSeq Nucleotide NM_001007156 (Hs), NM_008746 (Mm), NM_001270656 (Rn)
RefSeq Protein NP_001007157 (Hs), NP_877961 (Mm), NP_032772 (Mm), NP_001257585 (Rn)
UniProtKB Q16288 (Hs), Q6VNS1 (Mm), Q03351 (Rn)
Wikipedia NTRK3 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  NT3 binding domain of human TRKC receptor.
PDB Id:  1WWC
Resolution:  1.9Å
Species:  Human
References:  15
Image of receptor 3D structure from RCSB PDB
Description:  Discovery of a selective TRK Inhibitor with efficacy in rodent cancer tumor models: X-Ray diffraction with resolution of 2.20 Å
PDB Id:  3V5Q
Resolution:  2.2Å
Species:  Human
References:  1
Enzyme Reaction Click here for help
EC Number: 2.7.10.1
Natural/Endogenous Ligands Click here for help
neurotrophin-3 {Sp: Human}

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 16
⤷ pKd 8.0 (Kd 9.3x10-9 M) [16]
GW-2580 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.9 pKd 4
⤷ pKd 6.9 (Kd 1.2x10-7 M) [4]
zurletrectinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.7 pIC50 13
⤷ pIC50 9.7 (IC50 1.84x10-10 M) [13]
repotrectinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.7 pIC50 5
⤷ pIC50 9.7 (IC50 2.1x10-10 M) IC50 for TRKCG623R is 4.5 nM. [5]
GR-389988 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 9.3 pIC50 8
⤷ pIC50 9.3 (IC50 5x10-10 M) [8]
Description: In an off-chip mobility shift assay measuring inhibition of peptide substrate phosphorylation by the test compound in the presence ot recombinant human TrkC, catalytic domain [456-825].
taletrectinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.0 pIC50 9
⤷ pIC50 9.0 (IC50 9.8x10-10 M) [9]
emzeltrectinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition >9.0 pIC50 11
⤷ pIC50 >9.0 (IC50 <1x10-9 M) [11]
selitrectinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition >8.6 pIC50 12
⤷ pIC50 >8.6 (IC50 <2.5x10-9 M) [12]
CH7057288 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.6 pIC50 7
⤷ pIC50 8.6 (IC50 2.8x10-9 M) [7]
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 TrkC
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 7x10-9 M) [1]
RIPK1 inhibitor 22b Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.1 pIC50 10
⤷ pIC50 8.1 (IC50 7x10-9 M) [10]
NIK inhibitor 12f Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.3 pIC50 18
⤷ pIC50 7.3 (IC50 5.01x10-8 M) [18]
Description: Inhibitory concentration determined in a Reaction Biology kinase sreening assay.
pexidartinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.1 pIC50 14
⤷ pIC50 6.1 (IC50 8.9x10-7 M) [14]
ONO-7579 Small molecule or natural product N/A Inhibition - - 6
⤷ [6]
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: 4,17
Key to terms and symbols Click column headers to sort
Target used in screen: TRKC
Ligand Sp. Type Action Value Parameter
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.5 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.8 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.8 pKd
AST-487 Small molecule or natural product Hs Inhibitor Inhibition 7.5 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 7.2 pKd
crizotinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.1 pKd
GW-2580 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.9 pKd
doramapimod Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.7 pKd
dovitinib 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 6.7 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
Key to terms and symbols Click column headers to sort
Target used in screen: nd/TRKC
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
Gö 6976 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 0.2
indirubin derivative E804 Small molecule or natural product Hs Inhibitor Inhibition 1.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.0
Syk inhibitor Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 1.2
K-252a Small molecule or natural product Hs Inhibitor Inhibition 1.2
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 1.4
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 1.5
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.9
GSK-3 inhibitor XIII Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 2.0
indirubin-3'-monoxime Small molecule or natural product Hs Inhibitor Inhibition 2.2
Displaying the top 10 most potent ligands  View all ligands in screen »
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Congenital mesoblastic nephroma
Disease Ontology: DOID:4773
Orphanet: ORPHA2665
Disease:  Fibrosarcoma
Disease Ontology: DOID:3355
Orphanet: ORPHA2030

References

Show »

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. 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]

5. 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]

6. 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]

7. 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]

8. 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.

9. 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]

10. 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]

11. 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.

12. 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.

13. 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]

14. Tap WD, Wainberg ZA, Anthony SP, Ibrahim PN, Zhang C, Healey JH, Chmielowski B, Staddon AP, Cohn AL, Shapiro GI et al.. (2015) Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor. N Engl J Med, 373 (5): 428-37. [PMID:26222558]

15. 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]

16. 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]

17. 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]

18. Zhu Y, Ma Y, Zu W, Song J, Wang H, Zhong Y, Li H, Zhang Y, Gao Q, Kong B et al.. (2020) Identification of N-Phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine Derivatives as Novel, Potent, and Selective NF-κB Inducing Kinase (NIK) Inhibitors for the Treatment of Psoriasis. J Med Chem, 63 (13): 6748-6773. [PMID:32479083]

How to cite this page

Type VII RTKs: Neurotrophin receptor/Trk family: neurotrophic receptor tyrosine kinase 3. Last modified on 18/07/2024. Accessed on 12/10/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1819.