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Synonyms | N/A | Storage (From the date of receipt) |
3 years -20°C powder 1 years -80°C in solvent |
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化学式 | C26H23F2N3O4 |
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分子量 | 479.48 | CAS No. | 209984-57-6 | |
Solubility (25°C)* | 体外 | DMSO | 96 mg/mL (200.21 mM) | |
Ethanol | 20 mg/mL (41.71 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. |
製品説明 | 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. |
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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] |
キナーゼアッセイ | Assays for Aβ and NICD | |
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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. | ||
細胞アッセイ | 細胞株 | primary and immortalized KS cells |
濃度 | 500 μM | |
反応時間 | 24 hours | |
実験の流れ | 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. | |
動物実験 | 動物モデル | TgCRND8 mice model |
投薬量 | 1-10 mg/kg | |
投与方法 | Orally |
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Data from [Data independently produced by , , Exp Cell Res, 2017, 359(2):384-393]
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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人間や獣医の診断であるか治療的な使用のためにでない。
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