Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTZ3S8C)

• DTT Name: Presenilin 1 (PSEN1)
• Synonyms: S182 protein; Protein S182; Presenilin-1; PSNL1; PS1; PS-1; AD3
• Gene Name: PSEN1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Peptidase
• UniProt ID: PSN1_HUMAN
• TTD ID: T93105
• EC Number: EC 3.4.23.-
• Sequence:
  MTELPAPLSYFQNAQMSEDNHLSNTVRSQNDNRERQEHNDRRSLGHPEPLSNGRPQGNSR
  QVVEQDEEEDEELTLKYGAKHVIMLFVPVTLCMVVVVATIKSVSFYTRKDGQLIYTPFTE
  DTETVGQRALHSILNAAIMISVIVVMTILLVVLYKYRCYKVIHAWLIISSLLLLFFFSFI
  YLGEVFKTYNVAVDYITVALLIWNFGVVGMISIHWKGPLRLQQAYLIMISALMALVFIKY
  LPEWTAWLILAVISVYDLVAVLCPKGPLRMLVETAQERNETLFPALIYSSTMVWLVNMAE
  GDPEAQRRVSKNSKYNAESTERESQDTVAENDDGGFSEEWEAQRDSHLGPHRSTPESRAA
  VQELSSSILAGEDPEERGVKLGLGDFIFYSVLVGKASATASGDWNTTIACFVAILIGLCL
  TLLLLAIFKKALPALPISITFGLVFYFATDYLVQPFMDQLAFHQFYI
• Function: Requires the presence of the other members of the gamma-secretase complex for protease activity. Plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels. Stimulates cell-cell adhesion via its interaction with CDH1; this stabilizes the complexes between CDH1 (E-cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1 and JUP (gamma-catenin). Under conditions of apoptosis or calcium influx, cleaves CDH1. This promotes the disassembly of the complexes between CDH1 and CTNND1, JUP and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby negatively regulates Wnt signaling. Required for normal embryonic brain and skeleton development, and for normal angiogenesis. Mediates the proteolytic cleavage of EphB2/CTF1 into EphB2/CTF2. The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is therefore involved in calcium homeostasis. Involved in the regulation of neurite outgrowth. Is a regulator of presynaptic facilitation, spike transmission and synaptic vesicles replenishment in a process that depends on gamma-secretase activity. It acts through the control of SYT7 presynaptic expression. Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein).
• KEGG Pathway:
  Wnt signaling pathway (hsa04310)
  Notch signaling pathway (hsa04330)
  Neurotrophin signaling pathway (hsa04722)
  Alzheimer's disease (hsa05010)
• Reactome Pathway: Degradation of the extracellular matrix (R-HSA-1474228)

Molecular Interaction Atlas (MIA) of This DTT

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(S)-FLURBIPROFEN	DMF2O4T	Myalgia	FB56.2	Preregistration	[1]
R-flurbiprofen	DMFIVSR	N. A.	N. A.	Phase 2	[1]

9 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(2S,3R)-2-(benzyloxy)-3-methoxycyclohexanone	DMJE83O	Discovery agent	N.A.	Investigative	[2]
(5R,6S)-5,6-bis(benzyloxy)cyclohex-2-enone	DMREVX9	Discovery agent	N.A.	Investigative	[2]
(5R,6S)-6-(benzyloxy)-5-methoxycyclohex-2-enone	DMHG7MU	Discovery agent	N.A.	Investigative	[2]
1-benzoyl-2-benzyl-1,2-dihydropyridin-3(6H)-one	DMF9X2T	Discovery agent	N.A.	Investigative	[2]
1-Chloro-4-(1-phenyl-cyclohexanesulfonyl)-benzene	DM13HGN	Discovery agent	N.A.	Investigative	[3]
Drug 311383	DM5QUJV	Discovery agent	N.A.	Investigative	[4]
Drug 311440	DMOIFBK	Discovery agent	N.A.	Investigative	[4]
Drug 311951	DMXTCJ1	Discovery agent	N.A.	Investigative	[4]
Drug 311952	DM27ILS	Discovery agent	N.A.	Investigative	[4]

References

• [1] The geminal dimethyl analogue of Flurbiprofen as a novel Abeta42 inhibitor and potential Alzheimer's disease modifying agent. Bioorg Med Chem Lett. 2006 Apr 15;16(8):2219-23.
• [2] Novel gamma-secretase inhibitors discovered by library screening of in-house synthetic natural product intermediates. Bioorg Med Chem Lett. 2006 Jul 15;16(14):3813-6.
• [3] Aryl sulfones: a new class of gamma-secretase inhibitors. Bioorg Med Chem Lett. 2005 May 16;15(10):2685-8.
• [4] Discovery of a Subnanomolar helical D-tridecapeptide inhibitor of gamma-secretase. J Med Chem. 2004 Jul 29;47(16):3931-3.