Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTEDJN4)

• DTT Name: Low-affinity nerve growth factor receptor (NGFR)
• Synonyms: p75 ICD; Tumor necrosis factor receptor superfamily member 16; TNFRSF16; P75neurotrophin receptor (p75(NTR)); P75NTR; P75ICD; NGFreceptor; NGF-P75 receptor; NGF receptor; Lowaffinity neurotrophin receptor p75NTR; Low affinity neurotrophin receptor p75NTR; Gp80-LNGFR; CD271; 75kD-neurotrophin receptor
• Gene Name: NGFR
• DTT Type: Successful target; [1]
• BioChemical Class: Cytokine receptor
• UniProt ID: TNR16_HUMAN
• TTD ID: T50942
• Sequence:
  MGAGATGRAMDGPRLLLLLLLGVSLGGAKEACPTGLYTHSGECCKACNLGEGVAQPCGAN
  QTVCEPCLDSVTFSDVVSATEPCKPCTECVGLQSMSAPCVEADDAVCRCAYGYYQDETTG
  RCEACRVCEAGSGLVFSCQDKQNTVCEECPDGTYSDEANHVDPCLPCTVCEDTERQLREC
  TRWADAECEEIPGRWITRSTPPEGSDSTAPSTQEPEAPPEQDLIASTVAGVVTTVMGSSQ
  PVVTRGTTDNLIPVYCSILAAVVVGLVAYIAFKRWNSCKQNKQGANSRPVNQTPPPEGEK
  LHSDSGISVDSQSLHDQQPHTQTASGQALKGDGGLYSSLPPAKREEVEKLLNGSAGDTWR
  HLAGELGYQPEHIDSFTHEACPVRALLASWATQDSATLDALLAALRRIQRADLVESLCSE
  STATSPV
• Function: Low affinity receptor which can bind to NGF, BDNF, NT-3, and NT-4. Can mediate cell survival as well as cell death of neural cells. Necessary for the circadian oscillation of the clock genes ARNTL/BMAL1, PER1, PER2 and NR1D1 in the suprachiasmatic nucleus (SCN) of the brain and in liver and of the genes involved in glucose and lipid metabolism in the liver. Plays a role in the regulation of the translocation of GLUT4 to the cell surface in adipocytes and skeletal muscle cells in response to insulin, probably by regulating RAB31 activity, and thereby contributes to the regulation of insulin-dependent glucose uptake.
• KEGG Pathway:
  Ras signaling pathway (hsa04014)
  Rap1 signaling pathway (hsa04015)
  Cytokine-cytokine receptor interaction (hsa04060)
  PI3K-Akt signaling pathway (hsa04151)
  Neurotrophin signaling pathway (hsa04722)
  Transcriptional misregulation in cancer (hsa05202)
• Reactome Pathway:
  NRAGE signals death through JNK (R-HSA-193648)
  p75NTR negatively regulates cell cycle via SC1 (R-HSA-193670)
  Regulated proteolysis of p75NTR (R-HSA-193692)
  NADE modulates death signalling (R-HSA-205025)
  NRIF signals cell death from the nucleus (R-HSA-205043)
  p75NTR recruits signalling complexes (R-HSA-209543)
  NF-kB is activated and signals survival (R-HSA-209560)
  Axonal growth stimulation (R-HSA-209563)
  Axonal growth inhibition (RHOA activation) (R-HSA-193634)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Cenegermin	DM8Y2RU	Neurotrophic keratitis	9A74	Approved	[1]

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Fulranumab	DMK38MV	Arthralgia	ME82	Phase 3	[2]
SPI-205	DMHC2AW	Parkinson disease	8A00.0	Phase 2	[3]
LM11A-31	DM095HQ	Alzheimer disease	8A20	Phase 1/2	[4]

4 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Org-2766	DMVRA8N	Cognitive impairment	6D71	Discontinued in Phase 3	[5]
BU-4514N	DMJDMTK	Alzheimer disease	8A20	Terminated	[6]
CEP-427	DMTI10C	Alzheimer disease	8A20	Terminated	[2]
ReN-1820	DMWIAUK	Cystitis	GC00	Terminated	[7]

6 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ALD-901	DMAYGK9	Pain	MG30-MG3Z	Investigative	[2]
Axogenesis Factor-1	DMT5P8O	Cerebrovascular ischaemia	8B1Z	Investigative	[2]
CRB-0022	DMPWZOK	Pain	MG30-MG3Z	Investigative	[2]
Nerve growth factor conjugated RAP peptide	DM3AW8X	Neurodegenerative disorder	8A20-8A23	Investigative	[2]
TDI-0033	DMQ7VDM	Motor neurone disease	8B60	Investigative	[2]
TDI-0059	DMSI9QM	Motor neurone disease	8B60	Investigative	[2]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Parkinson's disease	8A00.0	Substantia nigra tissue	5.08E-01	0.38	0.37
Alzheimer's disease	8A00.0	Entorhinal cortex	3.92E-03	0.18	0.4
Interstitial cystitis	GA10	Bladder tissue	8.74E-03	0.55	2.56

References

• [1] 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
• [2] 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: 1888).
• [3] AIT-082 NeoTherapeutics Inc. IDrugs. 1998 Oct;1(6):694-9.
• [4] Small molecule p75NTR ligand prevents cognitive deficits and neurite degeneration in an Alzheimer's mouse model.Neurobiol Aging.2013 Aug;34(8):2052-63.
• [5] Effects of the ACTH4-9 analog Org2766 on brain plasticity: modulation of excitatory neurotransmission. Psychoneuroendocrinology. 1992 Aug;17(4):315-25.
• [6] A new neuritogenetic compound BU-4514N produced by Microtetraspora sp. J Antibiot (Tokyo). 1993 Jun;46(6):875-83.
• [7] Phosphorylation of Extracellular Signal-Regulated Kinases (pERK1/2) in Bladder Afferent Pathways with Cyclophosphamide (CYP)-Induced Cystitis. Neuroscience. 2009 November 10; 163(4): 1353-1362.