Target Information
Target General Information | Top | |||||
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Target ID |
T99204
(Former ID: TTDR00445)
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Target Name |
Presenilin 2 (PSEN2)
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Synonyms |
STM2; STM-2; Presenilin-2; PSNL2; PS-2; E5-1; AD5; AD4; AD3LP
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Gene Name |
PSEN2
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 3 Target-related Diseases | + | ||||
1 | Osteoarthritis [ICD-11: FA00-FA05] | |||||
2 | Shoulder lesion [ICD-11: FB53] | |||||
3 | Soft tissue disorder [ICD-11: FB56] | |||||
Function |
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 the nuclear membrane. May function in the cytoplasmic partitioning of proteins. The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is involved in calcium homeostasis. Is a regulator of mitochondrion-endoplasmic reticulum membrane tethering and modulates calcium ions shuttling between ER and mitochondria. 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 (amyloid-beta precursor protein).
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BioChemical Class |
Peptidase
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UniProt ID | ||||||
EC Number |
EC 3.4.23.-
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Sequence |
MLTFMASDSEEEVCDERTSLMSAESPTPRSCQEGRQGPEDGENTAQWRSQENEEDGEEDP
DRYVCSGVPGRPPGLEEELTLKYGAKHVIMLFVPVTLCMIVVVATIKSVRFYTEKNGQLI YTPFTEDTPSVGQRLLNSVLNTLIMISVIVVMTIFLVVLYKYRCYKFIHGWLIMSSLMLL FLFTYIYLGEVLKTYNVAMDYPTLLLTVWNFGAVGMVCIHWKGPLVLQQAYLIMISALMA LVFIKYLPEWSAWVILGAISVYDLVAVLCPKGPLRMLVETAQERNEPIFPALIYSSAMVW TVGMAKLDPSSQGALQLPYDPEMEEDSYDSFGEPSYPEVFEPPLTGYPGEELEEEEERGV KLGLGDFIFYSVLVGKAAATGSGDWNTTLACFVAILIGLCLTLLLLAVFKKALPALPISI TFGLIFYFSTDNLVRPFMDTLASHQLYI Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold |
Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
1 | (S)-FLURBIPROFEN | Drug Info | Preregistration | Myalgia | [2] | |
Mode of Action | [+] 1 Modes of Action | + | ||||
Inhibitor | [+] 11 Inhibitor drugs | + | ||||
1 | (S)-FLURBIPROFEN | Drug Info | [1] | |||
2 | R-flurbiprofen | Drug Info | [1] | |||
3 | (2S,3R)-2-(benzyloxy)-3-methoxycyclohexanone | Drug Info | [3] | |||
4 | (5R,6S)-5,6-bis(benzyloxy)cyclohex-2-enone | Drug Info | [3] | |||
5 | (5R,6S)-6-(benzyloxy)-5-methoxycyclohex-2-enone | Drug Info | [3] | |||
6 | 1-benzoyl-2-benzyl-1,2-dihydropyridin-3(6H)-one | Drug Info | [3] | |||
7 | 1-Chloro-4-(1-phenyl-cyclohexanesulfonyl)-benzene | Drug Info | [4] | |||
8 | Drug 311383 | Drug Info | [5] | |||
9 | Drug 311440 | Drug Info | [5] | |||
10 | Drug 311951 | Drug Info | [5] | |||
11 | Drug 311952 | Drug Info | [5] |
Cell-based Target Expression Variations | Top | |||||
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Cell-based Target Expression Variations |
Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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Notch signaling pathway | hsa04330 | Affiliated Target |
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Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
Neurotrophin signaling pathway | hsa04722 | Affiliated Target |
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Class: Organismal Systems => Nervous system | Pathway Hierarchy |
Degree | 10 | Degree centrality | 1.07E-03 | Betweenness centrality | 2.63E-04 |
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Closeness centrality | 2.26E-01 | Radiality | 1.40E+01 | Clustering coefficient | 3.56E-01 |
Neighborhood connectivity | 2.82E+01 | Topological coefficient | 1.41E-01 | Eccentricity | 12 |
Download | Click to Download the Full PPI Network of This Target | ||||
Chemical Structure based Activity Landscape of Target | Top |
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Drug Property Profile of Target | Top | |
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(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five |
Target Regulators | Top | |||||
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Target-interacting Proteins |
Target-Related Models and Studies | Top | |||||
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Target Validation |
References | Top | |||||
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REF 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. | |||||
REF 2 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025057) | |||||
REF 3 | 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. | |||||
REF 4 | Aryl sulfones: a new class of gamma-secretase inhibitors. Bioorg Med Chem Lett. 2005 May 16;15(10):2685-8. | |||||
REF 5 | Discovery of a Subnanomolar helical D-tridecapeptide inhibitor of gamma-secretase. J Med Chem. 2004 Jul 29;47(16):3931-3. |
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