Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTXABCW)

• DTT Name: NT-3 growth factor receptor (TrkC)
• Synonyms: TrkC tyrosine kinase; Trk-C; TRKC; Neurotrophic tyrosine kinase receptor type 3; NT3 growth factor receptor; GP145TrkC; GP145-TrkC
• Gene Name: NTRK3
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: NTRK3_HUMAN
• TTD ID: T51076
• EC Number: EC 2.7.10.1
• Sequence:
  MDVSLCPAKCSFWRIFLLGSVWLDYVGSVLACPANCVCSKTEINCRRPDDGNLFPLLEGQ
  DSGNSNGNASINITDISRNITSIHIENWRSLHTLNAVDMELYTGLQKLTIKNSGLRSIQP
  RAFAKNPHLRYINLSSNRLTTLSWQLFQTLSLRELQLEQNFFNCSCDIRWMQLWQEQGEA
  KLNSQNLYCINADGSQLPLFRMNISQCDLPEISVSHVNLTVREGDNAVITCNGSGSPLPD
  VDWIVTGLQSINTHQTNLNWTNVHAINLTLVNVTSEDNGFTLTCIAENVVGMSNASVALT
  VYYPPRVVSLEEPELRLEHCIEFVVRGNPPPTLHWLHNGQPLRESKIIHVEYYQEGEISE
  GCLLFNKPTHYNNGNYTLIAKNPLGTANQTINGHFLKEPFPESTDNFILFDEVSPTPPIT
  VTHKPEEDTFGVSIAVGLAAFACVLLVVLFVMINKYGRRSKFGMKGPVAVISGEEDSASP
  LHHINHGITTPSSLDAGPDTVVIGMTRIPVIENPQYFRQGHNCHKPDTYVQHIKRRDIVL
  KRELGEGAFGKVFLAECYNLSPTKDKMLVAVKALKDPTLAARKDFQREAELLTNLQHEHI
  VKFYGVCGDGDPLIMVFEYMKHGDLNKFLRAHGPDAMILVDGQPRQAKGELGLSQMLHIA
  SQIASGMVYLASQHFVHRDLATRNCLVGANLLVKIGDFGMSRDVYSTDYYRLFNPSGNDF
  CIWCEVGGHTMLPIRWMPPESIMYRKFTTESDVWSFGVILWEIFTYGKQPWFQLSNTEVI
  ECITQGRVLERPRVCPKEVYDVMLGCWQREPQQRLNIKEIYKILHALGKATPIYLDILG
• Function: Upon binding of its ligand NTF3/neurotrophin-3, NTRK3 autophosphorylates and activates different signaling pathways, including the phosphatidylinositol 3-kinase/AKT and the MAPK pathways, that control cell survival and differentiation. Receptor tyrosine kinase involved in nervous system and probably heart development.
• KEGG Pathway:
  Calcium signaling pathway (hsa04020)
  Neurotrophin signaling pathway (hsa04722)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  NGF-independant TRKA activation (R-HSA-187024)
  PI3K/AKT activation (R-HSA-198203)
  ARMS-mediated activation (R-HSA-170984)

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Entrectinib	DMMPTLH	Non-small-cell lung cancer	2C25	Approved	[2]
Larotrectinib	DM26CQR	Solid tumour/cancer	2A00-2F9Z	Approved	[1]

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MK-2461	DM21WBH	Alzheimer disease	8A20	Phase 1/2	[3]
Altiratinib	DMUJCBT	Solid tumour/cancer	2A00-2F9Z	Phase 1	[4]

10 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
3-amino-5-benzyl-substituted indazole derivative 1	DMFDURZ	Chronic pain	MG30	Patented	[5]
Azaindazole amide derivative 1	DMJWH4B	Chronic pain	MG30	Patented	[5]
Cyclopenta[d]pyrimidine derivative 1	DMKM6BY	N. A.	N. A.	Patented	[4]
PMID28270010-Compound-Figure24-b	DM0QHLK	N. A.	N. A.	Patented	[4]
PMID28270010-Compound-Figure5-1	DM2YAPJ	N. A.	N. A.	Patented	[4]
PMID28270010-Compound-Figure5-2	DMK3GRZ	N. A.	N. A.	Patented	[4]
PMID28270010-Compound-Figure5-3	DMSOT1R	N. A.	N. A.	Patented	[4]
PMID28270021-Compound-WO2015042088Example4	DM6KXOQ	Chronic pain	MG30	Patented	[5]
PMID28270021-Compound-WO2016054807Example1	DMD5QEL	Chronic pain	MG30	Patented	[5]
Pyrrolo[2,3-d]pyrimidine derivative 4	DME0WSR	Chronic pain	MG30	Patented	[5]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CEP-2563	DMH1PQ0	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 1	[6]

5 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AZD1332	DM0PVD9	Discovery agent	N.A.	Investigative	[7]
GNF-5837	DMYJO13	Discovery agent	N.A.	Investigative	[8]
JNJ-28312141	DMCMH7O	Discovery agent	N.A.	Investigative	[9]
PMID21493067C1d	DMFUQIT	Discovery agent	N.A.	Investigative	[10]
PMID24900538C2c	DM5PATM	Discovery agent	N.A.	Investigative	[11]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Alzheimer's disease	8A00.0	Entorhinal cortex	7.06E-04	-0.14	-0.43

References

• [1] 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
• [3] MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33.
• [4] Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Part I.Expert Opin Ther Pat. 2017 Jun;27(6):733-751.
• [5] Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Part II.Expert Opin Ther Pat. 2017 Jul;27(7):831-849.
• [6] Phase I clinical trial of CEP-2563 dihydrochloride, a receptor tyrosine kinase inhibitor, in patients with refractory solid tumors. Invest New Drugs. 2004 Nov;22(4):449-58.
• [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: 1817).
• [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.
• [9] 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. 2009 Nov;8(11):3151-61.
• [10] In vitro and in vivo evaluation of 6-aminopyrazolyl-pyridine-3-carbonitriles as JAK2 kinase inhibitors. Bioorg Med Chem Lett. 2011 May 15;21(10):2958-61.
• [11] Discovery of Disubstituted Imidazo[4,5-b]pyridines and Purines as Potent TrkA Inhibitors. ACS Med Chem Lett. 2012 Jul 26;3(9):705-9.