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neurotrophic receptor tyrosine kinase 1

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Target not currently curated in GtoImmuPdb

Target id: 1817

Nomenclature: neurotrophic receptor tyrosine kinase 1

Abbreviated Name: trkA

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 1 760 1q21-q22 NTRK1 neurotrophic receptor tyrosine kinase 1
Mouse 1 799 3 Ntrk1 neurotrophic tyrosine kinase, receptor, type 1
Rat 1 799 2q34 Ntrk1 neurotrophic receptor tyrosine kinase 1
Previous and Unofficial Names Click here for help
high affinity nerve growth factor receptor | high-affinity, slow-dissociating NGF receptor | MTC | neurotrophic tyrosine kinase | p140-TrkA | Tkr | TRK | tropomyosin-related kinase A
Database Links Click here for help
BRENDA
CATH/Gene3D
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Identification and structure of the nerve growth factor binding site on TrkA.
PDB Id:  1HE7
Resolution:  2.0Å
Species:  Human
References:  22
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the inactive TrkA kinase domain.
PDB Id:  4gt5
Resolution:  2.4Å
Species:  Human
References:  3
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of apo TrkA.
PDB Id:  4F0I
Resolution:  2.3Å
Species:  Human
References:  5
Enzyme Reaction Click here for help
EC Number: 2.7.10.1
Endogenous ligands (Human)
NGF (NGF, P01138) > 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 7.0 pKd 25
pKd 7.0 (Kd 1x10-7 M) [25]
GW-2580 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.2 pKd 8
pKd 6.2 (Kd 6.3x10-7 M) [8]
GR-389988 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 9.5 pIC50 14
pIC50 9.5 (IC50 3x10-10 M) [14]
Description: In a biochemical assay measuring inhibition of peptide substrate phosphorylation by the test compound in the presence ot recombinant human TrkA.
selitrectinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition >9.3 pIC50 19
pIC50 >9.3 (IC50 <5x10-10 M) [19]
repotrectinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.3 pIC50 9
pIC50 9.3 (IC50 5.3x10-10 M) IC50 for TRKAG595R is 2.7 nM [9]
DS-6051b Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.2 pIC50 15
pIC50 9.2 (IC50 6.2x10-10 M) [15]
gilteritinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition ~9.0 pIC50 16
pIC50 ~9.0 (IC50 ~1.1x10-9 M) [16]
compound 2c [PMID: 24900538] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.9 pIC50 24
pIC50 8.9 (IC50 1.4x10-9 M) [24]
compound 1d [PMID: 21493067] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.5 pIC50 23
pIC50 8.5 (IC50 3x10-9 M) [23]
CEP-11981 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.5 pIC50 12
pIC50 8.5 (IC50 3x10-9 M) [12]
AZD7451 Small molecule or natural product Hs Inhibition 8.5 pIC50 7
pIC50 8.5 (IC50 3x10-9 M) [7]
Description: In an Alphascreen assay using intracellular domain of a HIS-tagged human Trk A kinase (amino acids 442-796).
AZD1332 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition >8.3 pIC50 4
pIC50 >8.3 (IC50 <5x10-9 M) [4]
Description: NIH3T3 cells over expressing TrkA
sitravatinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.3 pIC50 21
pIC50 8.3 (IC50 5x10-9 M) [21]
Description: In a biochemical enzyme activity assay.
larotrectinib Small molecule or natural product Approved drug Hs Inhibition 8.0 pIC50 11
pIC50 8.0 (IC50 9.7x10-9 M) [11]
Description: Measured using a TrkA ELISA.
GNF-5837 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.0 pIC50 1
pIC50 8.0 (IC50 1.1x10-8 M) [1]
JNJ-28312141 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.8 pIC50 18
pIC50 7.8 (IC50 1.5x10-8 M) [18]
RIPK1 inhibitor 22b Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.6 pIC50 17
pIC50 7.6 (IC50 2.6x10-8 M) [17]
MK-2461 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.3 pIC50 20
pIC50 7.3 (IC50 4.6x10-8 M) [20]
milciclib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.3 pIC50 6
pIC50 7.3 (IC50 5.3x10-8 M) [6]
ONO-7579 Small molecule or natural product N/A Inhibition - - 13
[13]
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: 8,26

Key to terms and symbols Click column headers to sort
Target used in screen: TRKA
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 8.3 pKd
lestaurtinib Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 8.1 pKd
tozasertib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.4 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 7.3 pKd
crizotinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.0 pKd
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 7.0 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.0 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.8 pKd
KW-2449 Small molecule or natural product 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: 2,10

Key to terms and symbols Click column headers to sort
Target used in screen: TrkA/TRKA
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 0.8 0.0 0.0
Gö 6976 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.6 0.0 -1.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 2.3 0.0 1.0
indirubin derivative E804 Small molecule or natural product Hs Inhibitor Inhibition 3.8 -1.0 0.0
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 4.6
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 5.0 12.0 3.0
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 5.9 0.0 -1.0
Syk inhibitor Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 6.1 1.0 1.0
tozasertib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.5
SU11274 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.8 0.0 2.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immuno Process Associations
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0030183 B cell differentiation IEA
Immuno Process:  Immune system development
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0030183 B cell differentiation IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0030183 B cell differentiation IEA
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Hereditary sensory and autonomic neuropathy type 5
Synonyms: Hereditary sensory and autonomic neuropathy [Disease Ontology: DOID:11533]
Disease Ontology: DOID:11533
Orphanet: ORPHA64752
Disease:  Insensitivity to pain, congenital, with anhidrosis; CIPA
Synonyms: Hereditary sensory and autonomic neuropathy [Disease Ontology: DOID:11533]
Hereditary sensory and autonomic neuropathy type 4 [Orphanet: ORPHA642]
Disease Ontology: DOID:11533
OMIM: 256800
Orphanet: ORPHA642
Disease:  Thyroid carcinoma, familial medullary
Synonyms: Familial medullary thyroid carcinoma [Disease Ontology: DOID:0050547]
Disease Ontology: DOID:0050547
OMIM: 155240
Orphanet: ORPHA99361
Disease:  Thyroid carcinoma, papillary
Synonyms: Differentiated thyroid carcinoma [Orphanet: ORPHA146]
Papillary thyroid carcinoma [Disease Ontology: DOID:3969]
Disease Ontology: DOID:3969
OMIM: 188550
Orphanet: ORPHA146

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. Artim SC, Mendrola JM, Lemmon MA. (2012) Assessing the range of kinase autoinhibition mechanisms in the insulin receptor family. Biochem. J., 448 (2): 213-20. [PMID:22992069]

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

5. 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]

6. Brasca MG, Amboldi N, Ballinari D, Cameron A, Casale E, Cervi G, Colombo M, Colotta F, Croci V, D'Alessio R et al.. (2009) Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor. J. Med. Chem., 52 (16): 5152-63. [PMID:19603809]

7. Davies A, Ioannidis S, Lamb M, Su M, Wang T, Zhang H-J. (2013) 9-(pyrazol-3-yl)-9H-purine-2-amine and 3-(pyrazol-3-yl) -3H-imidazo[4,5-B] pyridin-5-amine derivatives and their use for the treatment of cancer. Patent number: US8486966B2. Assignee: AstraZeneca AB. Priority date: 04/05/2007. Publication date: 17/07/2013.

8. 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]

9. 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]

10. 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]

11. Haas J, Andrews SW, Jiang Y, Zhang G. (2010) Substituted pyrazolo[1,5-a]pyrimidine compounds as TRK kinase inhibitors. Patent number: WO2010048314 A1. Assignee: Array Biopharma Inc.. Priority date: 22/10/2008. Publication date: 29/04/2010.

12. 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]

13. 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]

14. 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.

15. 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]

16. Lee LY, Hernandez D, Rajkhowa T, Smith SC, Raman JR, Nguyen B, Small D, Levis M. (2017) Preclinical studies of gilteritinib, a next-generation FLT3 inhibitor. Blood, 129 (2): 257-260. [PMID:27908881]

17. 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]

18. Manthey CL, Johnson DL, Illig CR, Tuman RW, Zhou Z, Baker JF, Chaikin MA, Donatelli RR, Franks CF, Zeng L et al.. (2009) 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., 8 (11): 3151-61. [PMID:19887542]

19. 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.

20. 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]

21. Patwardhan PP, Ivy KS, Musi E, de Stanchina E, Schwartz GK. (2016) Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma. Oncotarget, 7 (4): 4093-109. [PMID:26675259]

22. Robertson AG, Banfield MJ, Allen SJ, Dando JA, Mason GG, Tyler SJ, Bennett GS, Brain SD, Clarke AR, Naylor RL et al.. (2001) Identification and structure of the nerve growth factor binding site on TrkA. Biochem. Biophys. Res. Commun., 282 (1): 131-41. [PMID:11263982]

23. Wang T, Ioannidis S, Almeida L, Block MH, Davies AM, Lamb ML, Scott DA, Su M, Zhang HJ, Alimzhanov M et al.. (2011) In vitro and in vivo evaluation of 6-aminopyrazolyl-pyridine-3-carbonitriles as JAK2 kinase inhibitors. Bioorg. Med. Chem. Lett., 21 (10): 2958-61. [PMID:21493067]

24. Wang T, Lamb ML, Block MH, Davies AM, Han Y, Hoffmann E, Ioannidis S, Josey JA, Liu ZY, Lyne PD et al.. (2012) Discovery of Disubstituted Imidazo[4,5-b]pyridines and Purines as Potent TrkA Inhibitors. ACS Med Chem Lett, 3 (9): 705-9. [PMID:24900538]

25. 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]

26. 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 1. Last modified on 21/08/2020. Accessed on 27/10/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1817.