Antibodies
Semagacestat (LY450139)
- 貨號 Cat. No.
- S1594
- 規格 Size
- 5~200mg
- 品牌 Brand
- Selleckchem
Description
Semagacestat (LY450139)
Semagacestat (LY450139) is a γ-secretase blocker for Aβ42, Aβ40 and Aβ38 with IC50 of 10.9 nM, 12.1 nM and 12.0 nM, also inhibits Notchsignaling with IC50 of 14.1 nM. Phase 3.
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Distributor Tel: +886-2-2827-1197jimmy@new.abscience.com.tw
Biological Activity
| Description | Semagacestat (LY450139) is a γ-secretase blocker for Aβ42, Aβ40 and Aβ38 with IC50 of 10.9 nM, 12.1 nM and 12.0 nM, also inhibits Notch signaling with IC50 of 14.1 nM. Phase 3. | |||||
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| Targets | Aβ42 | Aβ40 | Aβ38 | Notch | ||
| IC50 | 10.9 nM | 12.1 nM | 12.0 nM | 14.1 nM [1] | ||
| In vitro | Semagacestat reduces the secretion of Aβ42, Aβ40 and Aβ38 from H4 human glioma cells stably overexpressing human wild-type APP into the culture medium, with IC50 of 10.9 nM, 12.1 nM and 12.0 nM, respectively, without affecting cell viability. Semagacestat also increases β-CTF in cell lysates with ECmax of 16.0 nM, and the increase can be unexpectedly attenuated at high concentrations. Semagacestat inhibits Notch signaling with IC50 of 14.1 nM, and shows minimal Notch-sparing selectivity with Notch IC50/Aβ42 IC50 only 1.3. [1] Semagacestat causes a concentration-dependent decrease in Aβ40 secreted into the medium with IC50 of 111 nM from murine CTX expressing endogenous murine APP, but murine Aβ42 formation in CTX is roughly 12-fold less than Aβ40 in accordance with data for neurons from wild type mice. [2] | |||||
| In vivo | Oral administration of Semagacestat (1 mg/kg) to 5.5-month old APP-transgenic Tg2576 mice significantly ameliorates memory deficits on spatial working memory using the Y-maze task, which disappears after 8 days subchronic dosing. LY450139 decreases hippocampal levels of both Aβ42 and Aβ40 at 10 mg/kg (22-23% reduction) and 30 mg/kg (36-41% reduction) and increases β-CTF at 0.3-10 mg/kg in a dose dependent manner with no inhibition on the processing of other γ-secretase substrates, such as Notch, N-cadherin or EphA4, in the brain, but impairs normal cognition in wild-type mice and 3-month-old Tg2576 mice failing to restore cognitive deficits in the Y-maze test. [1] | |||||
| Features | The best characterized γ-secretase inhibitor that has reached the clinic. | |||||
Protocol(Only for Reference)
Kinase Assay: [1]
| Cellular APP processing assay and Notch signaling assay | H4 human glioma cells stably overexpressing human wild-type APP695 are treated with Semagacestat at various concentrations for 24 hours. Levels of Aβ42, Aβ40, and Aβ38 in the media are measured using separate ELISA kits. The expression vector of the constitutively active form of Notch (NotchΔE), encoding bases 1-60 and 5193-6657 of the human Notch1 coding region (NM_017617), is constructed into a pcDNA3.1 vector with a sequence modification from mouse to human. Notch signaling activity is evaluated using Cignal RBP-Jk Reporter Assay kit. RBP-Jk protein [CSL/CBF1/Su(H)/Lag1] is a transcription factor activated with Notch intracellular domain produced by γ-secretase. H4 cells are transiently transfected with the human NotchΔE expression vector and the RBP-Jk-responsive luciferase construct using Lipofectamine 2000, and then exposed to various concentrations of Semagacestat for 16 hours. Notch signaling is measured based on luciferase activity in the cell lysate using the Dual-Glo Luciferase Assay System. |
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Cell Assay: [2]
| Cell lines | Murine cortical neurons and cerebellar granule cells |
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| Concentrations | Dissolved in DMSO, final concentration ~10 μM |
| Incubation Time | 24 hours |
| Method | Cells are incubated with Semagacestat for 24 hours. For detection of cell viability, the percentage of viable cells is quantified by their capacity to reduce 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) following incubation with 0.5 mg/mL MTT for 60 minutes. For the detection of sAPP species, cells are lysed and analysed by western blotting. |
Animal Study: [1]
| Animal Models | Female Tg2576 mice expressing human APP695 with the Swedish mutation (K670N/M671L) |
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| Dosages | ~30 mg/kg |
| Administration | Orally administered once daily |
| Solubility | 0.5% methylcellulose, 30 mg/mL |
References
Clinical Trial Information( data from http://clinicaltrials.gov)
| NCT Number | Recruitment | Conditions | Sponsor /Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT00594568 | Completed | Alzheimer’s Disease | Eli Lilly and Company | 2008-03 | Phase 3 |
| NCT00762411 | Completed | Alzheimer’s Disease | Eli Lilly and Company | 2008-09 | Phase 3 |
| NCT01035138 | Completed | Alzheimer’s Disease | Eli Lilly and Company | 2009-12 | Phase 3 |
Chemical Information
Download Semagacestat (LY450139) SDF
| Molecular Weight (MW) | 361.44 |
|---|---|
| Formula | C19H27N3O4 |
| CAS No. | 425386-60-3 |
| Storage | 3 years -20℃Powder |
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| 6 months-80℃in DMSO | |
| Syonnyms | N/A |
| Solubility (25°C) * | In vitro | DMSO | 72 mg/mL (199 mM) |
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| Water | <1 mg/mL (<1 mM) | ||
| Ethanol | 41 mg/mL (113 mM) | ||
| In vivo | 0.5% methylcellulose, | 30 mg/mL | |
| * <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. | |||
| Chemical Name | (S)-2-hydroxy-3-methyl-N-((S)-1-((S)-3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-ylamino)-1-oxopropan-2-yl)butanamide |
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Preparing Stock Solutions
| Stock Solution (1ml DMSO) | 1mM | 10mM | 20mM | 30mM |
|---|---|---|---|---|
| Mass(mg) | 0.36144 | 3.6144 | 7.2288 | 10.8432 |
Customer Reviews (2)
 Click to enlarge | Rating | |
| Source | J Biol Chem, 2012, 287(15):11810-9. Semagacestat (LY450139) purchased from Selleck | |
| Method | cellular assay | |
| Cell Lines | HEK293 cells | |
| Concentrations | ||
| Incubation Time | 5 h | |
| Results | Semagacestat inhibited NICD translocation with high potency. |
Product Citations (2)
First and second generation γ-secretase modulators (GSMs) modulate amyloid-β (Aβ) peptide production through different mechanisms. [Borgegard T, et al. J Biol Chem 2012;287(15):11810-9]
Characterization of intermediate steps in Abeta production under near-native conditions. [Olsson F, et al. J Biol Chem 2014;289(3):1540-50]
