Semagacestat
Based on 12 publication(s) in Google Scholar
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.
Para uso exclusivo en investigación. No vendemos a pacientes.
- Pureza: 98.61%
- No. CAS: 425386-60-3
- Fòrmula: C19H27N3O4
- Peso molecular:361.44
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Almacenamiento:Powder -20°C, 3 years , 4°C, 2 years ; In solvent -80°C, 2 years , -20°C, 1 year
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Actividad biológica
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Chemical Information
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Solvente y solubilidad
- Protocolo
- Pureza y Documentación
- Referencias
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Help & FAQs
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Neuronal Signaling Compound Library
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Publications Citing Use of MedChemExpress (MCE) Semagacestat
More- EMBO Mol Med. 2017 Jul;9(7):950-966. [Abstract]
- EMBO J. 2012 May 16;31(10):2261-74. [Abstract]
- Cell Syst. 2018 Apr 25;6(4):424-443.e7. [Abstract]
- Molecules. 2013 Sep 3;18(9):10747-67. [Abstract]
- J Neurosci. 2015 Feb 11;35(6):2612-23. [Abstract]
- J Biol Chem. 2019 Jul 19;294(29):11276-11285. [Abstract]
- J Alzheimers Dis. 2012;28(4):809-22. [Abstract]
- J Alzheimers Dis. 2010;21(3):1005-12. [Abstract]
- Biochem Biophys Res Commun. 2024 Jan 15:692:149356. [Abstract]
- Neurol Res. 2019 Jun;41(6):489-497. [Abstract]
- Weill Medical College of Cornell University. 2026.
- ACS Comb Sci. 2019 Dec 9;21(12):805-816. [Abstract]
Customer Validation & Images
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WB
Actividad biológica
IC50: 10.9 nM (Aβ42), 12 nM (Aβ38), 12.1 nM (Aβ40), 14.1 nM (Notch)[1]
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Cell Line
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Type | Value | Description | References |
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| CHO | EC50 |
28 nM
Compound: LY-450139
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Inhibition of gamma-secretase expressed in CHO cells expressing wild type human recombinant APP assessed as amyloid beta40 aggregation
Inhibition of gamma-secretase expressed in CHO cells expressing wild type human recombinant APP assessed as amyloid beta40 aggregation
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[PMID: 18556202] |
| CHO | EC50 |
63 nM
Compound: LY-450139
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Inhibition of mouse notch expressed in CHO cells assessed as transactivation of soluble alkaline phosphatase reporter system
Inhibition of mouse notch expressed in CHO cells assessed as transactivation of soluble alkaline phosphatase reporter system
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[PMID: 18556202] |
| CHO | ED50 |
15 nM
Compound: 41
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Inhibition of gamma-secretase in CHO cells assessed expressing APPSw assessed as inhibition of amyloid beta(1 to x) secretion after overnight incubation by ELISA
Inhibition of gamma-secretase in CHO cells assessed expressing APPSw assessed as inhibition of amyloid beta(1 to x) secretion after overnight incubation by ELISA
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[PMID: 23713656] |
| CHO | ED50 |
220 nM
Compound: 41
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Inhibition of gamma-secretase in CHO cells assessed expressing NotchdeltaE assessed as inhibition of notch cleavage after overnight incubation by luciferase reporter gene assay
Inhibition of gamma-secretase in CHO cells assessed expressing NotchdeltaE assessed as inhibition of notch cleavage after overnight incubation by luciferase reporter gene assay
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[PMID: 23713656] |
| SH-SY5Y | IC50 |
38 nM
Compound: 16 LY-450139
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Displacement of [3H]5-chloro-N-((2S,3R)-5,5,5-trifluoro-1-hydroxy-3-methylpentan-2-yl)thiophene-2-sulfonamide from gamma secretase in human SH-SY5Y cells by competitive binding assay
Displacement of [3H]5-chloro-N-((2S,3R)-5,5,5-trifluoro-1-hydroxy-3-methylpentan-2-yl)thiophene-2-sulfonamide from gamma secretase in human SH-SY5Y cells by competitive binding assay
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[PMID: 19694467] |
| SH-SY5Y | IC50 |
38 nM
Compound: 16 LY-450139
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Inhibition of gamma secretase-mediated amyloid beta (1 to 40) production in human SH-SY5Y cells
Inhibition of gamma secretase-mediated amyloid beta (1 to 40) production in human SH-SY5Y cells
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[PMID: 19694467] |
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.
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
| NCT Number | Sponsor | Condition | Start Date |
Phase
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|---|---|---|---|---|
| NCT01329991 | Plexxikon| | 2011-05 | PHASE1 |
Chemical Information
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No. CAS 425386-60-3
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Appearance Solid
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Peso molecular 361.44
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Fòrmula C19H27N3O4
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Color White to off-white
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SMILES
O=C([C@H]1NC([C@@H](NC([C@H](C(C)C)O)=O)C)=O)N(CCC2=C1C=CC=C2)C
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Synonyms
LY450139
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Powder -20°C 3 years 4°C 2 years In solvent -80°C 2 years -20°C 1 year
Publications (12)
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Journal Impact Factor
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Most Recent
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EMBO Mol Med
γ-Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct. [Abstract]2017 Jul;9(7):950-966. PMID: 28539479
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).
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EMBO J
2012 May 16;31(10):2261-74. PMID: 22505025 -
Cell Syst
A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations. [Abstract]2018 Apr 25;6(4):424-443.e7. PMID: 29655704 -
Molecules
New flurbiprofen derivatives: synthesis, membrane affinity and evaluation of in vitro effect on β-amyloid levels. [Abstract]2013 Sep 3;18(9):10747-67. PMID: 24005968 -
J Neurosci
Posttraumatic stress disorder-like induction elevates β-amyloid levels, which directly activates corticotropin-releasing factor neurons to exacerbate stress responses. [Abstract]2015 Feb 11;35(6):2612-23. PMID: 25673853 -
J Biol Chem
Individual and combined presenilin 1 and 2 knockouts reveal that both have highly overlapping functions in HEK293T cells. [Abstract]2019 Jul 19;294(29):11276-11285. PMID: 31167792 -
J Alzheimers Dis
2012;28(4):809-22. PMID: 22072214 -
J Alzheimers Dis
Acute effect on the Aβ isoform pattern in CSF in response to γ-secretase modulator and inhibitor treatment in dogs. [Abstract]2010;21(3):1005-12. PMID: 20634579 -
Biochem Biophys Res Commun
Utility of human induced pluripotent stem cell-derived small intestinal epithelial cells for pharmacokinetic, toxicological, and immunological studies. [Abstract]2024 Jan 15:692:149356. PMID: 38071890 -
Neurol Res
The long-non-coding RNA NEAT1 is a novel target for Alzheimer's disease progression via miR-124/BACE1 axis. [Abstract]2019 Jun;41(6):489-497. PMID: 31014193 -
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ACS Comb Sci
Benzimidazolyl-pyrazolo[3,4- b]pyridinones, Selective Inhibitors of MOLT-4 Leukemia Cell Growth and Sea Urchin Embryo Spiculogenesis: Target Quest. [Abstract]2019 Dec 9;21(12):805-816. PMID: 31689077
Solvente y solubilidad
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.
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.
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.
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
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.
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.
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.
Please enter the basic information of animal experiments:
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Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
Please enter your animal formula composition:
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%DMSO +
Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
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%+
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+%Tween-80 + +
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%Saline +
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).
Working solution concentration: 0.22 mg/mL
Method for preparing stock solution: mg drug dissolved in μL DMSO. Stock solution concentration: mg/mL.
1. Take μL DMSO stock solution;
2. Add μL .
μL , mix evenly;
3. Then add μL Tween 80, mix evenly;
4. Then add μL
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.
Protocolo
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].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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.
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
Pureza y Documentación
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Ficha de datos (284 KB)
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SDS (393 KB)
- English - EN (393 KB)
- Français - FR (393 KB)
- Deutsch - DE (393 KB)
- Norwegian - NO (393 KB)
- Español - ES (393 KB)
- Swedish - SV (393 KB)
- Italian - IT (393 KB)
- Korean - KR (393 KB)
- Portuguese - PT (393 KB)
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Instrucciones de manejo (2659 KB)
Referencias
[1]. Mitani Y, et al. Differential effects between γ-secretase inhibitors and modulators on cognitive function in amyloid precursor protein-transgenic and nontransgenic mice. J Neurosci. 2012 Feb 8;32(6):2037-50. [Content Brief]
[2]. Elvang AB, et al. Differential effects of gamma-secretase and BACE1 inhibition on brain Abeta levels in vitro and in vivo. J Neurochem. 2009 Sep;110(5):1377-87. [Content Brief]
[3]. Justice NJ, et al. Posttraumatic stress disorder-like induction elevates β-amyloid levels, which directly activates corticotropin-releasing factor neurons to exacerbate stress responses. J Neurosci. 2015 Feb 11;35(6):2612-23. [Content Brief]
[4]. Portelius E, et al. Acute effect on the Aβ isoform pattern in CSF in response to γ-secretase modulator and inhibitor treatment in dogs. J Alzheimers Dis. 2010;21(3):1005-12. [Content Brief]
[5]. Junki Hirano, et al. Characterization of SPP inhibitors suppressing propagation of HCV and protozoa. Proc Natl Acad Sci U S A. 2017 Dec12;114(50):E10782-E10791. [Content Brief]
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 |
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| 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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