LY411575

Catalog No.S2714 Batch:S271402

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Technical Data

Formula

C26H23F2N3O4
Molecular Weight 479.48 CAS No. 209984-57-6
Solubility (25°C)* In vitro DMSO 95 mg/mL (198.13 mM)
Ethanol 95 mg/mL (198.13 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 LY411575 is a potent γ-secretase inhibitor with IC50 of 0.078 nM/0.082 nM (membrane/cell-based), also inhibits Notch cleavage with IC50 of 0.39 nM in APP or NΔE expressing HEK293 cells. LY411575 induces apoptosis.
Targets
γ secretase [1]
(HEK293 cells expressing either APP or NΔE)		 γ secretase [1]
(HEK293 cells expressing either APP or NΔE)		 Notch S3 cleavage [1]
(HEK293 cells expressing either APP or NΔE)
0.078 nM 0.082 nM 0.39 nM
In vitro LY-411575 inhibits γ-secretase which can be assessed by the substrates like amyloid precursor protein (APP) and Notch S3 cleavage. [1] LY-411575, which blocks Notch activation, results in apoptosis in primary and immortalized KS cells. [2]
In vivo 10 mg/kg oral dose of LY-411575 decreases brain and plasma Aβ40 and -42 dose-dependently. [1] LY-411575 reduces cortical Aβ40 in young (preplaque) transgenic CRND8 mice (ED50 ≈ 0.6 mg/kg) and produces significant thymus atrophy and intestinal goblet cell hyperplasia at higher doses (>3 mg/kg). The therapeutic window is similar after oral and subcutaneous administration and in young and aged CRND8 mice. Both the thymus and intestinal side effects are reversible after a 2-week washout period. Three-week treatment with 1 mg/kg LY411575 reduces cortical Aβ40 by 69% without inducing intestinal effects, although a previously unreported change in coat color is observed. [3]

Protocol (from reference)

Kinase Assay:

[1]
  • Assays for Aβ and NICD

    Procedures for measuring γ-secretase activity in membranes prepared from HEK293 cells expressing APP have been described previously (Zhang L et al Biochemistry 40, 5049-5055). Intact HEK293 cells expressing either APP or NΔE are treated with various concentrations of LY- 411,575 for 4 hours at 37 °C. In the case of cells expressing NΔE, cells are lysed, the cell lysates are separated on a 4-12% NuPAGE gel, and the processed NICD fragment is detected via Western blot with a cleavage site-specific antibody. The inhibition of NICD production is quantified by spot densitometric analysis using FluorChem. In the case of cells expressing APP, the conditioned medium is collected, centrifuged at 10,000 × g for 5 minutes to remove cell debris, and stored at -20 °C prior to the determination of Aβ levels. Aβ40 and -42 produced in HEK293 membrane- and cell-based assays, as well as plasma Aβ40 and cortex Aβ40 from TgCRND8 mice, are analyzed without pretreatment using an electrochemiluminescence detection-based immunoassay. Plasma Aβ42 is measured by enzyme-linked immunosorbent assay. A commercially available enzyme-linked immunosorbent assay kit is used to measure cortex Aβ42 according to the manufacturer''s instructions.
Cell Assay:

[2]
  • Cell lines

    primary and immortalized KS cells

  • Concentrations

    500 μM

  • Incubation Time

    24 hours

  • Method

    DNA/PI staining is performed using standard methodologies. Briefly, 1 × 106 cells are permeabilized with 100% ethanol in the presence of 15% FBS. The cells are washed and then treated for 15 minutes at 37 °C with 10 mg/mL RNAse. PI (5 mg/mL) is added, and the cells incubated for 1 hour at 4 °C prior to analysis by flow cytometry with 10 000 cells analysed per gated determination. The results are confirmed using the Immunotech Annexin V staining kit following the manufacturers’ instructions. At least three independent experiments are performed showing similar results.

Animal Study:

[1]
  • Animal Models

    TgCRND8 mice model

  • Dosages

    1-10 mg/kg

  • Administration

    Orally

Customer Product Validation

Data from [Data independently produced by , , Exp Cell Res, 2017, 359(2):384-393]

Selleck's LY411575 has been cited by 37 publications

Tolerable glycometabolic stress boosts cancer cell resilience through altered N-glycosylation and Notch signaling activation [ Cell Death Dis, 2024, 15(1):53] PubMed: 38225221
Akt3 activation by R-Ras in an endothelial cell enforces quiescence and barrier stability of neighboring endothelial cells via Jagged1 [ Cell Rep, 2024, 43(3):113837] PubMed: 38402584
Molecular mechanism underlying miR-204-5p regulation of adipose-derived stem cells differentiation into cells from three germ layers [ Cell Death Discov, 2024, 10(1):95] PubMed: 38388551
CD151 expression marks atrial- and ventricular- differentiation from human induced pluripotent stem cells [ Commun Biol, 2024, 7(1):231] PubMed: 38418926
Stepwise emergence of the neuronal gene expression program in early animal evolution [ Cell, 2023, S0092-8674(23)00917-0] PubMed: 37729907
Neuronal γ-secretase regulates lipid metabolism, linking cholesterol to synaptic dysfunction in Alzheimer's disease [ Neuron, 2023, S0896-6273(23)00513-5] PubMed: 37543038
Stromal-induced epithelial-mesenchymal transition induces targetable drug resistance in acute lymphoblastic leukemia [ Cell Rep, 2023, 42(7):112804] PubMed: 37453060
Zebrafish functional xenograft vasculature platform identifies PF-502 as a durable vasculature normalization drug [ iScience, 2023, 26(9):107734] PubMed: 37680473
The ndrg2 Gene Regulates Hair Cell Morphogenesis and Auditory Function during Zebrafish Development [ Int J Mol Sci, 2023, 24(12)10002] PubMed: 37373150
Decoding pancreatic endocrine cell differentiation and β cell regeneration in zebrafish [ Sci Adv, 2023, 9(33):eadf5142] PubMed: 37595046

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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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