Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT9PB26)

• DTT Name: Presynaptic density protein 95 (DLG4)
• Synonyms: Synapse-associated protein 90; SAP90; SAP-90; Postsynaptic density-95; Postsynaptic density protein 95; PSD95; PSD-95; Disks large homolog 4; Discs, large homolog 4
• Gene Name: DLG4
• DTT Type: Clinical trial target; [1]
• Related Disease:
  Cerebral ischaemia [ICD-11: 8B1Z]
  Ischaemic/haemorrhagic stroke [ICD-11: 8B20]
• BioChemical Class: Ezrin/radixin/moesin-binding phosphoprotein 50
• UniProt ID: DLG4_HUMAN
• TTD ID: T04507
• Sequence:
  MDCLCIVTTKKYRYQDEDTPPLEHSPAHLPNQANSPPVIVNTDTLEAPGYELQVNGTEGE
  MEYEEITLERGNSGLGFSIAGGTDNPHIGDDPSIFITKIIPGGAAAQDGRLRVNDSILFV
  NEVDVREVTHSAAVEALKEAGSIVRLYVMRRKPPAEKVMEIKLIKGPKGLGFSIAGGVGN
  QHIPGDNSIYVTKIIEGGAAHKDGRLQIGDKILAVNSVGLEDVMHEDAVAALKNTYDVVY
  LKVAKPSNAYLSDSYAPPDITTSYSQHLDNEISHSSYLGTDYPTAMTPTSPRRYSPVAKD
  LLGEEDIPREPRRIVIHRGSTGLGFNIVGGEDGEGIFISFILAGGPADLSGELRKGDQIL
  SVNGVDLRNASHEQAAIALKNAGQTVTIIAQYKPEEYSRFEAKIHDLREQLMNSSLGSGT
  ASLRSNPKRGFYIRALFDYDKTKDCGFLSQALSFRFGDVLHVIDASDEEWWQARRVHSDS
  ETDDIGFIPSKRRVERREWSRLKAKDWGSSSGSQGREDSVLSYETVTQMEVHYARPIIIL
  GPTKDRANDDLLSEFPDKFGSCVPHTTRPKREYEIDGRDYHFVSSREKMEKDIQAHKFIE
  AGQYNSHLYGTSVQSVREVAEQGKHCILDVSANAVRRLQAAHLHPIAIFIRPRSLENVLE
  INKRITEEQARKAFDRATKLEQEFTECFSAIVEGDSFEEIYHKVKRVIEDLSGPYIWVPA
  RERL
• Function: Required for synaptic plasticity associated with NMDA receptor signaling. Overexpression or depletion of DLG4 changes the ratio of excitatory to inhibitory synapses in hippocampal neurons. May reduce the amplitude of ASIC3 acid-evoked currents by retaining the channel intracellularly. May regulate the intracellular trafficking of ADR1B. Also regulates AMPA-type glutamate receptor (AMPAR) immobilization at postsynaptic density keeping the channels in an activated state in the presence of glutamate and preventing synaptic depression. Interacts with the cytoplasmic tail of NMDA receptor subunits and shaker-type potassium channels.
• KEGG Pathway:
  Hippo signaling pathway (hsa04390)
  Glutamatergic synapse (hsa04724)
  Huntington's disease (hsa05016)
  Cocaine addiction (hsa05030)
• Reactome Pathway:
  Unblocking of NMDA receptor, glutamate binding and activation (R-HSA-438066)
  CREB phosphorylation through the activation of CaMKII (R-HSA-442729)
  Ras activation uopn Ca2+ infux through NMDA receptor (R-HSA-442982)
  RHO GTPases activate CIT (R-HSA-5625900)
  RAF/MAP kinase cascade (R-HSA-5673001)
  Trafficking of AMPA receptors (R-HSA-399719)

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Tat-NR2B9c	DMD6AUX	Cerebrovascular ischaemia	8B1Z	Phase 3	[1], [2], [3]

18 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2-Methyl-2,4-Pentanediol	DMD45CU	Discovery agent	N.A.	Investigative	[4]
FETAV	DMO1N2T	Discovery agent	N.A.	Investigative	[5]
Guanosine-5'-Monophosphate	DM3SLZK	Discovery agent	N.A.	Investigative	[4]
KSG-LDTKNYKQTSV	DM5DTMQ	Discovery agent	N.A.	Investigative	[5]
KSG-YEKLSSIESDV	DMPLFRC	Discovery agent	N.A.	Investigative	[5]
N-(3,4-Dichlorophenyl)propyl-ETAV	DMTERF6	Discovery agent	N.A.	Investigative	[5]
N-(3,4-Difluorophenyl)propyl-ETAV	DMF2D4O	Discovery agent	N.A.	Investigative	[5]
N-(Naphthalene-2-yl)ethyl-ETAV	DMG8KXR	Discovery agent	N.A.	Investigative	[5]
N-Benzyl-ETAV	DMNPS4R	Discovery agent	N.A.	Investigative	[5]
N-Butyl-ETAV	DMY3HEF	Discovery agent	N.A.	Investigative	[5]
N-Cyclohexylethyl-ETAV	DMCH5M1	Discovery agent	N.A.	Investigative	[5]
N-Cyclohexylmethyl-ETAV	DMIC8Z6	Discovery agent	N.A.	Investigative	[5]
N-Ethyl-ETAV	DMPTNI8	Discovery agent	N.A.	Investigative	[5]
N-Methyl-ETAV	DMP1EF6	Discovery agent	N.A.	Investigative	[5]
N-Phenylethyl-ETAV	DM1VSO9	Discovery agent	N.A.	Investigative	[5]
N-Phenylpropyl-ETAV	DM90GNC	Discovery agent	N.A.	Investigative	[5]
N-Propyl-ETAV	DMUTDNV	Discovery agent	N.A.	Investigative	[5]
YGRKKRRQRRR-KLSSIESDV	DMV89B4	Discovery agent	N.A.	Investigative	[5]

References

• [1] Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain. Nature. 2012 Feb 29;483(7388):213-7.
• [2] Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science. 1995 Sep 22;269(5231):1737-40.
• [3] Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science. 1999 Jun 11;284(5421):1845-8.
• [4] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [5] Modified peptides as potent inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction. J Med Chem. 2008 Oct 23;51(20):6450-9.