Target General Infomation
Target ID
T93105
Former ID
TTDR00444
Target Name
Presenilin 1
Gene Name
PSEN1
Synonyms
PS-1; PS1; S182 protein; PSEN1
Target Type
Clinical Trial
Function
Probable 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 (beta-amyloid precursor protein). Requires the other members of the gamma-secretase complex to have a protease activity. May play a role in intracellular signaling and gene expression or in linking chromatin to thenuclear membrane. Stimulates cell-cell adhesion though its association with the E-cadherin/catenin complex. Under conditions of apoptosis or calcium influx, cleaves E-cadherin promoting the disassembly of the E-cadherin/catenin complex and increasing the pool of cytoplasmic beta-catenin, thus negatively regulating Wnt signaling. May also play a role in hematopoiesis.
BioChemical Class
Peptidase
Target Validation
T93105
UniProt ID
EC Number
EC 3.4.23.-
Sequence
MTELPAPLSYFQNAQMSEDNHLSNTVRSQNDNRERQEHNDRRSLGHPEPLSNGRPQGNSR
QVVEQDEEEDEELTLKYGAKHVIMLFVPVTLCMVVVVATIKSVSFYTRKDGQLIYTPFTE
DTETVGQRALHSILNAAIMISVIVVMTILLVVLYKYRCYKVIHAWLIISSLLLLFFFSFI
YLGEVFKTYNVAVDYITVALLIWNFGVVGMISIHWKGPLRLQQAYLIMISALMALVFIKY
LPEWTAWLILAVISVYDLVAVLCPKGPLRMLVETAQERNETLFPALIYSSTMVWLVNMAE
GDPEAQRRVSKNSKYNAESTERESQDTVAENDDGGFSEEWEAQRDSHLGPHRSTPESRAA
VQELSSSILAGEDPEERGVKLGLGDFIFYSVLVGKASATASGDWNTTIACFVAILIGLCL
TLLLLAIFKKALPALPISITFGLVFYFATDYLVQPFMDQLAFHQFYI
Drugs and Mode of Action
Drug(s) R-flurbiprofen Drug Info Phase 2 Discovery agent [521532], [542364]
Inhibitor (2S,3R)-2-(benzyloxy)-3-methoxycyclohexanone Drug Info [528191]
(5R,6S)-5,6-bis(benzyloxy)cyclohex-2-enone Drug Info [528191]
(5R,6S)-6-(benzyloxy)-5-methoxycyclohex-2-enone Drug Info [528191]
(S)-FLURBIPROFEN Drug Info [528008]
1-benzoyl-2-benzyl-1,2-dihydropyridin-3(6H)-one Drug Info [528191]
1-Chloro-4-(1-phenyl-cyclohexanesulfonyl)-benzene Drug Info [527542]
Drug 311383 Drug Info [527143]
Drug 311440 Drug Info [527143]
Drug 311951 Drug Info [527143]
Drug 311952 Drug Info [527143]
R-flurbiprofen Drug Info [528008]
Pathways
KEGG Pathway Wnt signaling pathway
Notch signaling pathway
Neurotrophin signaling pathway
Alzheimer&#039
s disease
NetPath Pathway Notch Signaling Pathway
PANTHER Pathway Alzheimer disease-amyloid secretase pathway
Alzheimer disease-presenilin pathway
Notch signaling pathway
Pathway Interaction Database Notch signaling pathway
Presenilin action in Notch and Wnt signaling
p75(NTR)-mediated signaling
Syndecan-3-mediated signaling events
Reactome Degradation of the extracellular matrix
WikiPathways Notch Signaling Pathway
Notch Signaling Pathway
Alzheimers Disease
References
Ref 521532ClinicalTrials.gov (NCT00045123) R-Flurbiprofen in Treating Patients With Localized Prostate Cancer at Risk of Recurrence. U.S. National Institutes of Health.
Ref 542364(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. (Ligand id: 7340).
Ref 527143J Med Chem. 2004 Jul 29;47(16):3931-3.Discovery of a Subnanomolar helical D-tridecapeptide inhibitor of gamma-secretase.
Ref 527542Bioorg Med Chem Lett. 2005 May 16;15(10):2685-8.Aryl sulfones: a new class of gamma-secretase inhibitors.
Ref 528008Bioorg Med Chem Lett. 2006 Apr 15;16(8):2219-23. Epub 2006 Feb 7.The geminal dimethyl analogue of Flurbiprofen as a novel Abeta42 inhibitor and potential Alzheimer's disease modifying agent.
Ref 528191Bioorg Med Chem Lett. 2006 Jul 15;16(14):3813-6. Epub 2006 May 8.Novel gamma-secretase inhibitors discovered by library screening of in-house synthetic natural product intermediates.

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