Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTKN7QR)

• DTT Name: BDNF/NT-3 growth factors receptor (TrkB)
• Synonyms: Tropomyosin-related kinase B; TrkB tyrosine kinase; Trk-B; TRKB; Neurotrophic tyrosine kinase receptor type 2; GP145-TrkB
• Gene Name: NTRK2
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: NTRK2_HUMAN
• TTD ID: T84703
• EC Number: EC 2.7.10.1
• Sequence:
  MSSWIRWHGPAMARLWGFCWLVVGFWRAAFACPTSCKCSASRIWCSDPSPGIVAFPRLEP
  NSVDPENITEIFIANQKRLEIINEDDVEAYVGLRNLTIVDSGLKFVAHKAFLKNSNLQHI
  NFTRNKLTSLSRKHFRHLDLSELILVGNPFTCSCDIMWIKTLQEAKSSPDTQDLYCLNES
  SKNIPLANLQIPNCGLPSANLAAPNLTVEEGKSITLSCSVAGDPVPNMYWDVGNLVSKHM
  NETSHTQGSLRITNISSDDSGKQISCVAENLVGEDQDSVNLTVHFAPTITFLESPTSDHH
  WCIPFTVKGNPKPALQWFYNGAILNESKYICTKIHVTNHTEYHGCLQLDNPTHMNNGDYT
  LIAKNEYGKDEKQISAHFMGWPGIDDGANPNYPDVIYEDYGTAANDIGDTTNRSNEIPST
  DVTDKTGREHLSVYAVVVIASVVGFCLLVMLFLLKLARHSKFGMKGPASVISNDDDSASP
  LHHISNGSNTPSSSEGGPDAVIIGMTKIPVIENPQYFGITNSQLKPDTFVQHIKRHNIVL
  KRELGEGAFGKVFLAECYNLCPEQDKILVAVKTLKDASDNARKDFHREAELLTNLQHEHI
  VKFYGVCVEGDPLIMVFEYMKHGDLNKFLRAHGPDAVLMAEGNPPTELTQSQMLHIAQQI
  AAGMVYLASQHFVHRDLATRNCLVGENLLVKIGDFGMSRDVYSTDYYRVGGHTMLPIRWM
  PPESIMYRKFTTESDVWSLGVVLWEIFTYGKQPWYQLSNNEVIECITQGRVLQRPRTCPQ
  EVYELMLGCWQREPHMRKNIKGIHTLLQNLAKASPVYLDILG
• Function: Receptor for BDNF/brain-derived neurotrophic factor and NTF4/neurotrophin-4. Alternatively can also bind NTF3/neurotrophin-3 which is less efficient in activating the receptor but regulates neuron survival through NTRK2. Upon ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades. Through SHC1, FRS2, SH2B1, SH2B2 activates the GRB2-Ras-MAPK cascade that regulates for instance neuronal differentiation including neurite outgrowth. Through the same effectors controls the Ras-PI3 kinase-AKT1 signaling cascade that mainly regulates growth and survival. Through PLCG1 and the downstream protein kinase C-regulated pathways controls synaptic plasticity. Thereby, plays a role in learning and memory by regulating both short term synaptic function and long-term potentiation. PLCG1 also leads to NF-Kappa-B activation and the transcription of genes involved in cell survival. Hence, it is able to suppress anoikis, the apoptosis resulting from loss of cell-matrix interactions. May also play a role in neutrophin-dependent calcium signaling in glial cells and mediate communication between neurons and glia. Receptor tyrosine kinase involved in the development and the maturation of the central and the peripheral nervous systems through regulation of neuron survival, proliferation, migration, differentiation, and synapse formation and plasticity.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  Neurotrophin signaling pathway (hsa04722)
  Alcoholism (hsa05034)
• Reactome Pathway: NGF-independant TRKA activation (R-HSA-187024)

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]

1 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]

11 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	[4]
Azaindazole amide derivative 1	DMJWH4B	Chronic pain	MG30	Patented	[4]
Cyclopenta[d]pyrimidine derivative 1	DMKM6BY	N. A.	N. A.	Patented	[5]
Macrocycle derivative 13	DM1KBSV	Cell proliferative disorder	FB86	Patented	[5]
PMID28270010-Compound-Figure24-b	DM0QHLK	N. A.	N. A.	Patented	[5]
PMID28270010-Compound-Figure5-1	DM2YAPJ	N. A.	N. A.	Patented	[5]
PMID28270010-Compound-Figure5-2	DMK3GRZ	N. A.	N. A.	Patented	[5]
PMID28270010-Compound-Figure5-3	DMSOT1R	N. A.	N. A.	Patented	[5]
PMID28270021-Compound-WO2015042088Example4	DM6KXOQ	Chronic pain	MG30	Patented	[4]
PMID28270021-Compound-WO2016054807Example1	DMD5QEL	Chronic pain	MG30	Patented	[4]
Pyrrolo[2,3-d]pyrimidine derivative 4	DME0WSR	Chronic pain	MG30	Patented	[4]

4 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AZD1332	DM0PVD9	Discovery agent	N.A.	Investigative	[6]
GNF-5837	DMYJO13	Discovery agent	N.A.	Investigative	[7]
PMID24432909C8e	DMEGAZS	Discovery agent	N.A.	Investigative	[8]
TrkB NAM	DMBZI5F	Neurodegenerative disorder	8A20-8A23	Investigative	[6]

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	3.06E-01	-0.15	-0.31

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 II.Expert Opin Ther Pat. 2017 Jul;27(7):831-849.
• [5] Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Part I.Expert Opin Ther Pat. 2017 Jun;27(6):733-751.
• [6] 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: 1818).
• [7] 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.
• [8] Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib. J Med Chem.> 2014 Feb 27;57(4):1170-87.