1. Neuronal Signaling Stem Cell/Wnt
  2. γ-secretase Amyloid-β Notch
  3. Semagacestat

Semagacestat  (Synonyms: LY450139)

Cat. No.: HY-10009 Purity: 98.89%
COA Handling Instructions

Semagacestat is a γ-secretase inhibitor, inhibits β-amyloid (Aβ42), Aβ38 and Aβ40 with IC50s of 10.9, 12 and 12.1 nM, respectively; also inhibits Notch signaling with IC50 of 14.1 nM. Semagacestat can be used for the research of alzheimer's disease.

For research use only. We do not sell to patients.

Semagacestat Chemical Structure

Semagacestat Chemical Structure

CAS No. : 425386-60-3

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Solid + Solvent
10 mM * 1 mL in DMSO
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10 mM * 1 mL in DMSO USD 56 In-stock
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10 mg USD 130 In-stock
50 mg USD 450 In-stock
100 mg USD 750 In-stock
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Customer Review

Based on 12 publication(s) in Google Scholar

Top Publications Citing Use of Products

    Semagacestat purchased from MedChemExpress. Usage Cited in: EMBO Mol Med. 2017 Jul;9(7):950-966.  [Abstract]

    Turnover of endogenous CD74 P8 is inhibited by RO4929079 and BMS-906024. Cell lysate Western blot of A20 cells treated with GSIs is developed with In-1 antibody. MK-0752 and Semagacestat tests used the same control lane (0 nM).
    • Biological Activity

    • Protocol

    • Purity & Documentation

    • References

    • Customer Review

    Description

    Semagacestat is a γ-secretase inhibitor, inhibits β-amyloid (Aβ42), Aβ38 and Aβ40 with IC50s of 10.9, 12 and 12.1 nM, respectively; also inhibits Notch signaling with IC50 of 14.1 nM. Semagacestat can be used for the research of alzheimer's disease[1].

    IC50 & Target

    IC50: 10.9 nM (Aβ42), 12 nM (Aβ38), 12.1 nM (Aβ40), 14.1 nM (Notch)[1]

    In Vitro

    Semagacestat (LY450139) reduces the secretion of Aβ42, Aβ40, and Aβ38 in 96-well-cultured media and increases β-CTF in cell lysates as expected, although this increase is unexpectedly attenuated at high concentrations[1].
    In cortical neurons (CTX), Semagacestat (LY450139) causes a concentration-dependent decrease in Aβ40 secreted into the medium with IC50 value 111 nM for Semagacestat. Semagacestat causes a concentration-dependent decrease in Aβ40 and Aβ42 secreted into the medium with an IC50 value of 126 and 130 nM, respectively[2].
    Semagacestat (3 Μm; for 4 days) exhibits no significant cell toxicity in Huh7 cells[5].

    MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

    In Vivo

    Semagacestat (LY450139) is found to decrease both Aβ42 and Aβ40 at 10 mg/kg (22-23% reduction;p<0.01) and increase β-CTF at 0.3-10 mg/kg in a dose-dependent manner (15-162% elevation; p<0.01 at 1-10 mg/kg)[1]. The γ-secretase inhibitor, Semagacestat (LY450139), a highly potent low molecular weight compound, significantly reduces β-amyloid (Aβ) levels in cell cultures permanently over-expressing APP and in both wildtype and transgenic APP-expressing mice. Three hours following p.o. dosing of 30 mg/kg Semagacestat levels of Aβ40 are reduced by 43% (unpaired t-test, p=0.002) in the brains of wildtype C57BL/6 mice compare with vehicle treated controls. Subcutaneous administration of Semagacestat (30 mg/kg) transiently decreases the amounts of Aβ40 in the dialysate with a maximum reduction in Aβ40 levels of 80% at 3 h post-dosing (p<0.001)[2].

    MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

    Clinical Trial
    Molecular Weight

    361.44

    Formula

    C19H27N3O4

    CAS No.
    Appearance

    Solid

    Color

    White to off-white

    SMILES

    O=C([C@H]1NC([C@@H](NC([C@H](C(C)C)O)=O)C)=O)N(CCC2=C1C=CC=C2)C

    Shipping

    Room temperature in continental US; may vary elsewhere.

    Storage
    Powder -20°C 3 years
    4°C 2 years
    In solvent -80°C 2 years
    -20°C 1 year
    Solvent & Solubility
    In Vitro: 

    DMSO : ≥ 100 mg/mL (276.67 mM; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

    *"≥" means soluble, but saturation unknown.

    Preparing
    Stock Solutions
    Concentration Solvent Mass 1 mg 5 mg 10 mg
    1 mM 2.7667 mL 13.8336 mL 27.6671 mL
    5 mM 0.5533 mL 2.7667 mL 5.5334 mL
    View the Complete Stock Solution Preparation Table

    * Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
    Storage method and period of stock solution: -80°C, 2 years; -20°C, 1 year. When stored at -80°C, please use it within 2 years. When stored at -20°C, please use it within 1 year.

    • Molarity Calculator

    • Dilution Calculator

    Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)

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    Concentration (start) × Volume (start) = Concentration (final) × Volume (final)

    This equation is commonly abbreviated as: C1V1 = C2V2

    Concentration (start)

    C1

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    Volume (start)

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    In Vivo:

    Select the appropriate dissolution method based on your experimental animal and administration route.

    For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
    To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for in vivo experiments, it is recommended to prepare freshly and use it on the same day.
    The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.

    • Protocol 1

      Add each solvent one by one:  10% DMSO    40% PEG300    5% Tween-80    45% Saline

      Solubility: ≥ 3 mg/mL (8.30 mM); Clear solution

      This protocol yields a clear solution of ≥ 3 mg/mL (saturation unknown).

      Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (30.0 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.

      Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
    • Protocol 2

      Add each solvent one by one:  10% DMSO    90% (20% SBE-β-CD in Saline)

      Solubility: ≥ 3 mg/mL (8.30 mM); Clear solution

      This protocol yields a clear solution of ≥ 3 mg/mL (saturation unknown).

      Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (30.0 mg/mL) to 900 μL 20% SBE-β-CD in Saline, and mix evenly.

      Preparation of 20% SBE-β-CD in Saline (4°C, storage for one week): 2 g SBE-β-CD powder is dissolved in 10 mL Saline, completely dissolve until clear.
    In Vivo Dissolution Calculator
    Please enter the basic information of animal experiments:

    Dosage

    mg/kg

    Animal weight
    (per animal)

    g

    Dosing volume
    (per animal)

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    Number of animals

    Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
    Please enter your animal formula composition:
    %
    DMSO +
    +
    %
    Tween-80 +
    %
    Saline
    Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
    The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).
    Calculation results:
    Working solution concentration: mg/mL
    Method for preparing stock solution: mg drug dissolved in μL  DMSO (Stock solution concentration: mg/mL).
    The concentration of the stock solution you require exceeds the measured solubility. The following solution is for reference only. If necessary, please contact MedChemExpress (MCE).
    Method for preparing in vivo working solution for animal experiments: Take μL DMSO stock solution, add μL . μL , mix evenly, next add μL Tween 80, mix evenly, then add μL Saline.
     If the continuous dosing period exceeds half a month, please choose this protocol carefully.
    Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
    Purity & Documentation

    Purity: 98.89%

    References
    Kinase Assay
    [1]

    H4 human glioma cells stably overexpressing human wild-type APP695 are maintained in DMEM supplemented with 10% fetal bovine serum and penicillin/streptomycin. Cells are cultured in 96- or 6-well plates overnight, and then treated with each drug (e.g., Semagacestat) at various concentrations for 24 h. Levels of Aβ1-42, Aβ1-40, and Aβ1-38 in the media are measured using separate ELISA kits. To quantify β-CTF, cells are lysed with RIPA buffer (25 mM Tris, 150 mM NaCl, 1% NP-40, 1% sodium deoxycholate, 0.1% SDS; pH 7.6) containing Complete protease inhibitor mixture and applied to a human β-CTF ELISA kit at 1:20 dilution. Aliquots of the cell lysate are also used for CellTiter-Glo Luminescent Cell Viability Assay. The cell lysate from the six-well plate is subjected to Western blot analysis[1].

    MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Cell Assay
    [2]

    Murine cortical neurons (CTX) are isolated from day 14 to 16 foetal C57BL/6 mice. Briefly, dissociated neurons are plated on 100 μg/mL poly-L-lysine coated dishes at a density of 0.25×106 cells/cm2 (800000 cells/mL; 100 μL/well, 96-well plate) and cultured in Neurobasal medium supplemented with 2% B-27 supplement without antioxidants, 0.5 mM L-glutamine and 100 U/mL penicillin and 0.1 mg/mL streptomycin. Neurons are fed every third day by replacing half of the medium. The proportion of glia cells in the cultures is less than 10%, as assessed by an antibody against glia-fibrillary acidic protein. CTX are used at 6 days in vitro (DIV) after complete medium change and incubated with secretase inhibitors (e.g., Semagacestat) for 24 h. Neurons and cell medium are used at DIV 7. For detection of cell viability, the percentage of viable cells is quantified by their capacity to reduce MTT following incubation with 0.5 mg/mL MTT for 60 min. Viability is routinely measured after all in vitro pharmacological experiments[2].

    MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Animal Administration
    [1]

    Mice[1]
    Female Tg2576 mice expressing human APP695 with the Swedish mutation (K670N/M671L) are used. Male transgenic mice are procured and crossbred with female B6SJLF1/J mice. To identify drug effects on cognitive function, four different experiments are conducted. The objective of Experiment 1 is to elucidate acute and subchronic drug effects on cognitive deficits in Tg2576 mice. Each drug (Semagacestat, BMS-708163, and GSM-2) is orally administered to 5.5-month-old Tg2576 mice for 8 d. Y-maze tests are conducted to evaluate spatial working memory 3 h after administration on days 1 and 8. Vehicle-treated Tg2576 mice demonstrates significantly lower spontaneous alternation rates than WT mice in the Y-maze test, suggesting deficits in spatial working memory. On day 1, 1 mg/kg Semagacestat, 1 mg/kg BMS-708163, and 0.1-0.3 mg/kg GSM-2 significantly ameliorates these cognitive deficits (acute effects). On day 8, however, the GSI effects disappear, whereas GSM-2 retained its significant effects (subchronic effects). Mice are killed immediately after the Y-maze test on day 8, when hippocampal levels of Aβ42, Aβ40, and β-CTF are determined by ELISA.

    MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    References

    Complete Stock Solution Preparation Table

    * Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
    Storage method and period of stock solution: -80°C, 2 years; -20°C, 1 year. When stored at -80°C, please use it within 2 years. When stored at -20°C, please use it within 1 year.

    Optional Solvent Concentration Solvent Mass 1 mg 5 mg 10 mg 25 mg
    DMSO 1 mM 2.7667 mL 13.8336 mL 27.6671 mL 69.1678 mL
    5 mM 0.5533 mL 2.7667 mL 5.5334 mL 13.8336 mL
    10 mM 0.2767 mL 1.3834 mL 2.7667 mL 6.9168 mL
    15 mM 0.1844 mL 0.9222 mL 1.8445 mL 4.6112 mL
    20 mM 0.1383 mL 0.6917 mL 1.3834 mL 3.4584 mL
    25 mM 0.1107 mL 0.5533 mL 1.1067 mL 2.7667 mL
    30 mM 0.0922 mL 0.4611 mL 0.9222 mL 2.3056 mL
    40 mM 0.0692 mL 0.3458 mL 0.6917 mL 1.7292 mL
    50 mM 0.0553 mL 0.2767 mL 0.5533 mL 1.3834 mL
    60 mM 0.0461 mL 0.2306 mL 0.4611 mL 1.1528 mL
    80 mM 0.0346 mL 0.1729 mL 0.3458 mL 0.8646 mL
    100 mM 0.0277 mL 0.1383 mL 0.2767 mL 0.6917 mL
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      Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

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