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Semagacestat

Catalog No. T6125   CAS 425386-60-3
Synonyms: LY450139

Semagacestat (LY450139) (LY450139) is a γ-secretase blocker for Aβ42/Aβ40/Aβ38 (IC50: 10.9/12.1/12.0 nM) and also inhibits Notch signaling (IC50: 14.1 nM).

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Semagacestat Chemical Structure
Semagacestat, CAS 425386-60-3
Pack Size Availability Price/USD Quantity
2 mg In stock $ 34.00
5 mg In stock $ 55.00
10 mg In stock $ 105.00
25 mg In stock $ 198.00
50 mg In stock $ 369.00
100 mg In stock $ 549.00
1 mL * 10 mM (in DMSO) In stock $ 44.00
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Purity: 99.11%
Purity: 97.1%
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Biological Description
Chemical Properties
Storage & Solubility Information
Description Semagacestat (LY450139) (LY450139) is a γ-secretase blocker for Aβ42/Aβ40/Aβ38 (IC50: 10.9/12.1/12.0 nM) and also inhibits Notch signaling (IC50: 14.1 nM).
Targets&IC50 γ secretase(Aβ42):10.9 nM, γ secretase(Aβ38):12.0 nM, γ secretase(Aβ40):12.1 nM
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]
Kinase Assay 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.
Cell Research 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.(Only for Reference)
Synonyms LY450139
Molecular Weight 361.44
Formula C19H27N3O4
CAS No. 425386-60-3

Storage

Powder: -20°C for 3 years | In solvent: -80°C for 1 year

Solubility Information

H2O: < 1 mg/mL (insoluble or slightly soluble)

DMSO: 67 mg/mL (185.4 mM)

Ethanol: 39 mg/mL (107.9 mM)

TargetMolReferences and Literature

1. Mitani Y, et al. J Neurosci, 2012, 32(6), 2037-2050. 2. Elvang AB, et al. J Neurochem, 2009, 110(5), 1377-1387.

Related compound libraries

This product is contained In the following compound libraries:
Anti-Cancer Clinical Compound Library Anti-Cancer Drug Library Anti-Neurodegenerative Disease Compound Library NO PAINS Compound Library Reprogramming Compound Library Anti-Alzheimer's Disease Compound Library HIF-1 Signaling Pathway Compound Library Anti-Aging Compound Library Neuronal Differentiation Compound Library Anti-Cancer Compound Library

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Keywords

Semagacestat 425386-60-3 Neuroscience Proteases/Proteasome Stem Cells Beta Amyloid Gamma-secretase LY-450139 Inhibitor inhibit LY 450139 γ-secretase LY450139 β-amyloid peptide Notch Gamma secretase Amyloid-β Abeta inhibitor

 

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