PVtCD-cTP-AlkF-2
PVtCD-cTP-AlkF-2 is a ROS-responsive DAPK1 BmTAC activator with blood-brain barrier permeability. PVtCD-cTP-AlkF-2 is equipped with a VHL E3 ubiquitin ligase ligand modified with a ROS-responsive phenylboronic acid caging group, and undergoes uncaging activation only in a high-ROS microenvironment. PVtCD-cTP-AlkF-2 can selectively recognize and degrade dephosphorylated activated DAPK1. PVtCD-cTP-AlkF-2 exerts its activator function through caveolae-mediated transcytosis. PVtCD-cTP-AlkF-2 reduces APP and Tau phosphorylation, decreases Aβ oligomer deposition, and improves cognitive function in aged APP/PS1 mice. PVtCD-cTP-AlkF-2 can be used for research on Alzheimer's disease.
(Pink: DAPK1 ligand (HY-P12376); Blue: VHL E3 ligase ligand; Black: linker (HY-22408)).
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- Formule: C218H321BF12N60O54S3
- Masse moléculaire:4981.24
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Activité biologique
Description
IC50 & Target
[1]|
DAPK1 |
In Vitro
PVtCD-cTP-AlkF-2 (100 μM H2O2; 24 h) is stable at pH 7.4 but undergoes nearly complete ROS-responsive decaging[1].
PVtCD-cTP-AlkF-2 (2.5-20 μM; 0-36 h) reduced total DAPK1 by 62% and selectively degraded activated DAPK1 through proteasome- and ROS-dependent mechanisms, thereby reversing downstream APP and Tau phosphorylation in Aβ42 oligomer-exposed SH-SY5Y cells[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. Further protocols information, click here.
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Cell Line:SH-SY5Y human neuroblastoma cells
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Concentration:0, 2.5, 5, 10, 20 μM (dose-dependent)
10 μM (time-dependent) -
Incubation Time:24 h
0, 6, 12, 24, 36 h -
Result:Degraded DAPK1 protein in Aβ42 oligomer-treated SH-SY5Y cells in a dose-dependent and time-dependent manner, while p-DAPK1(Ser308) remains largely unaffected.
In Vivo
PVtCD-cTP-AlkF-2 (1.8 mg/kg; i.v.; five injections on days 0-12; up to day 30) produces age-dependent DAPK1 degradation in the Aβ42 oligomer-induced AD mouse model, achieving 81% DAPK1 reduction in aged mice[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:APP/PS1 transgenic (aged 12-month-old)[1]
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Dosage:100 μM, 100 μL
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Administration:i.v.; five doses on days 0, 3, 6, 9, and 12; until day 30
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Result:Achieved a 55% reduction in DAPK1 protein levels.
Degraded DAPK1 predominantly in NeuN-positive neurons.
Did not significantly alter phosphorylated DAPK1 (Ser308) or CaMKII protein levels.
Suppressed APP and Tau phosphorylation markedly.
Reduced Aβ oligomer deposition significantly.
Showed preserved neuronal morphology and increased Nissl body content in hippocampus and cortex by Nissl staining.
Showed a significantly greater proportion of swimming distance in the target quadrant in Morris water maze.
Enhanced nest-building quality.
Identified 100 upregulated and 74 downregulated proteins by proteomic analysis, enriched in pathways governing neuron survival, autophagy, energy metabolism, inflammation, and synaptic plasticity.
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Animal Model:Aβ42 oligomer‑lesioned mice (established by stereotaxic hippocampal injection of Cy5‑labelled Aβ42 oligomers (100 μM, 100 μL))[1]
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Dosage:1.8 mg/kg (100 μM, 100 μL)
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Administration:i.v.; five doses on days 0, 3, 6, 9, and 12; until day 30
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Result:Produced age-dependent DAPK1 degradation in the Aβ42 oligomer-induced AD mouse model, achieving 81% DAPK1 reduction in aged mice.
Chemical Information
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Masse moléculaire 4981.24
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Formule C218H321BF12N60O54S3
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SMILES
OC1=CC=C(C[C@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@H](CCCCN)NC([C@@H](CC2)CC[C@@H]2C(N[C@H](C(N3[C@@H](C[C@H](C3)OC(OCC4=CC=C(B(O)O)C=C4)=O)C(NCC5=CC=C(C6=C(C)N=CS6)C=C5)=O)=O)C(C)(C)C)=O)=O)=O)CCCCN)=O)CC(N)=O)=O)CCCNC(N)=N)=O)CC(N)=O)=O)CCCCN)=O)CC(C)C)=O)CCCNC(N)=N)=O)CCCNC(N)=N)=O)CCC(N)=O)=O)CC7=CNC=N7)=O)CO)=O)C(NCCCCCC(N[C@H]8CSC(C9=O)CC(N9CCC(OCC(F)(C(F)(C(F)(C(F)(C(F)(C(F)(COC(CCN%10C(CC(C%10=O)SC[C@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC8=O)CC%11=CNC=N%11)=O)CC(C)C)=O)CC(N)=O)=O)[C@H](CC)C)=O)CC(C)C)=O)CO)=O)[C@@H](C)O)=O)CC(C)C)=O)CC%12=CNC%13=CC=CC=C%13%12)=O)CCCCN)=O)CC%14=CC=C(O)C=C%14)=O)CCCNC(N)=N)=O)C(N)=O)=O)=O)F)F)F)F)F)F)=O)=O)=O)=O)C=C1
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Protocole
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Kinase activity and phosphorylation assays
Kinase activity assays measure the ability of kinases to transfer phosphate groups from ATP to specific substrates, while phosphorylation assays detect the presence and levels of phosphorylated proteins. Common methods include radiolabeled ATP incorporation (e. g. ,), ADP release detection via bioluminescence (e. g. ,[3]), enzyme-linked immunosorbent assays (ELISA) for phospho-specific epitopes (e. g. ,[6]), and microtiter-based formats for high-throughput screening (e. g. ,[8]). The ADP-Glo assay quantifies kinase activity by measuring ADP produced during phosphorylation using a luciferase-based system. Radiometric assays involve autoradiography or scintillation counting after incorporation of 32P-labeled ATP into substrate proteins. ELISA-based approaches rely on phospho-specific antibodies to detect activated kinases in cell lysates or purified samples.
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Western Blot
Western blotting (WB) is a commonly used experimental method in molecular biology, biochemistry, and immunogenetics for identifying and quantifying target proteins. It combines gel electrophoresis with immunoassay, enabling researchers to analyze protein expression, post-translational modifications, and molecular weight.
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ROS/oxidative-stress fluorescent staining
ROS/oxidative-stress fluorescent staining uses cell-permeant fluorogenic probes that become fluorescent after oxidation inside cells or tissues; commonly used examples include DCFH-DA/DCFDA for broad cellular oxidant detection, DHE for superoxide-related signal detection, MitoSOX for mitochondrial superoxide-related signal detection, and CellROX probes for oxidative-stress-associated fluorescence readouts. The assay detects probe oxidation rather than a single ROS species unless the probe and analysis method have been chemically validated for that species. DCFH-DA enters cells, is deacetylated by intracellular esterases to DCFH, and produces fluorescent DCF after oxidation, so the readout is used as an operational measure of total cellular oxidative stress rather than a species-specific ROS measurement. DHE and MitoSOX can report superoxide-related oxidation, but red fluorescence alone can include non-specific ethidium-like oxidation products; HPLC or optimized spectral approaches are
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Protocol for Water Maze
The Morris Water Maze is a rodent spatial learning and memory assay in which a mouse or rat swims in opaque water to find an escape platform; in the hidden-platform version, the animal cannot see the platform and must use distal extra-maze cues to learn its fixed spatial location. The assay primarily measures hippocampus-dependent spatial learning during acquisition trials and spatial reference memory during probe trials after platform removal; readouts include escape latency, swim path length, swim speed, quadrant occupancy, platform-site crossings, and proximity to the former platform location.
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Transepithelial/transendothelial electrical resistance assay
TEER measures electrical resistance across epithelial or endothelial monolayers cultured on permeable supports, and the readout reflects ionic conductance through the cell barrier, especially the paracellular pathway regulated by junctional integrity. TEER can be measured without destroying the monolayer and is commonly used before or during transport, permeability, barrier-disruption, and barrier-maturation experiments. TEER values are influenced by biological maturation and technical conditions; reported factors include temperature, medium formulation, passage number, electrode geometry, membrane properties, and junctional length during early monolayer maturation. Therefore, TEER should be interpreted with blank-insert subtraction, area normalization, repeated readings, and, when possible, orthogonal barrier readouts such as FITC-dextran flux or tight-junction staining.
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Protocol for Kinase activity and phosphorylation assays
Kinase activity assays measure transfer of phosphate from ATP to a protein or peptide substrate, generating phosphorylated substrate, ADP, or incorporated radiolabeled phosphate as the readout; phosphorylation assays measure site-specific phosphorylation in cells or tissues as a proxy for kinase-pathway activation, inhibition, or substrate regulation. Phosphorylation can be detected by phospho-specific Western blot, immunoprecipitation kinase assay, phospho-immunofluorescence, phospho-flow cytometry, luminescent ADP detection, radiolabeled ATP incorporation, or reporter-based pathway assays, and these readouts can be applied to cancer cells, primary neurons, mouse tumors, organoids, inflammatory macrophages, ferroptosis studies, and mitophagy studies when the kinase target is biologically relevant.
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Alzheimer’s Disease Modeling
Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by a progressive decline in cognitive functions and loss of specific types of neurons and synapses. Alzheimer's symptoms can be simulated in mice by injecting drugs (such as Aβ) or genetically modified.
Pureté et documentation
Références
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)