Semagacestat (LY450139)

Catalog No.S1594 Batch:S159401

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Technical Data

Formula

C19H27N3O4
Molecular Weight 361.44 CAS No. 425386-60-3
Solubility (25°C)* In vitro DMSO 72 mg/mL (199.2 mM)
Ethanol 43 mg/mL (118.96 mM)
Water Insoluble
* <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.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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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 in H4 human glioma cell. Phase 3.
Targets
Aβ42 [1]
(H4 human glioma cells)		 Aβ38 [1]
(H4 human glioma cells)		 Aβ40 [1]
(H4 human glioma cells)		 Notch [1]
(H4 human glioma cells)
10.9 nM 12.0 nM 12.1 nM 14.1 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]
Features The best characterized γ-secretase inhibitor that has reached the clinic.

Protocol (from 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.
Cell Assay:[2]
  • Cell lines

    Murine cortical neurons and cerebellar granule cells

  • 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)

  • Dosages

    ~30 mg/kg

  • Administration

    Orally administered once daily

Customer Product Validation

Data from [J Biol Chem, 2014, 289(3), 1540-50]

Data from [J Biol Chem, 2012, 287(15), 11810-9]

Data from [Data independently produced by , , J Biol Chem, 2016, 291(4):1538-51.]

Selleck's Semagacestat (LY450139) has been cited by 21 publications

Simultaneous Inhibition of Ceramide Hydrolysis and Glycosylation Synergizes to Corrupt Mitochondrial Respiration and Signal Caspase Driven Cell Death in Drug-Resistant Acute Myeloid Leukemia [ Cancers (Basel), 2023, 15(6)1883] PubMed: 36980769
Establishment and characterization of immortalized sweat gland myoepithelial cells [ Sci Rep, 2022, 12(1):7] PubMed: 34997030
LY450139 Inhibited Ti-Particle-Induced Bone Dissolution via Suppressing Notch and NF-κB Signaling Pathways [ Calcif Tissue Int, 2022, 111(2):211-223] PubMed: 35588014
TrkA-mediated endocytosis of p75-CTF prevents cholinergic neuron death upon γ-secretase inhibition [ Life Sci Alliance, 2021, 4(4)e202000844] PubMed: 33536237
Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway. [ Cancer Cell, 2020, 13;37(1):104-122e12] PubMed: 31935369
Amyloidogenic Processing of Alzheimer's Disease β-amyloid Precursor Protein Induces Cellular Iron Retention [ Mol Psychiatry, 2020, 10.1038/s41380-020-0762-0] PubMed: 32444869
A novel human colon signet-ring cell carcinoma organoid line: establishment, characterization and application [ Carcinogenesis, 2020, 41(7):993-1004] PubMed: 31740922
In Vitro Evaluation of Clinical Candidates of γ-Secretase Inhibitors: Effects on Notch Inhibition and Promoting Beige Adipogenesis and Mitochondrial Biogenesis [ Pharm Res, 2020, 37(10):185] PubMed: 32888109
DRUGPATH - a novel bioinformatic approach identifies DNA-damage pathway as a regulator of size maintenance in human ESCs and iPSCs [ Sci Rep, 2019, 9(1):1897] PubMed: 30760778
Porphyromonas gingivalis in Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. [ Sci Adv, 2019, 5(1):eaau3333] PubMed: 30746447

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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