product name LY411575
Description: LY411575, also known as LSN-411575, is a potent, cell permeable and selective γ-secretase inhibitor with IC50 of 0.078 nM/0.082 nM (membrane/cell-based), it also inhibits Notch cleavage with IC50 of 0.39 nM in APP or NΔE expressing HEK293 cells. LY 411575 reduces Aβ/42 after acute or chronic treatment, and blocks Notch activation.
References: J Biol Chem. 2004 Mar 26;279(13):12876-82; Oncogene. 2005 Sep 22;24(42):6333-44; J Pharmacol Exp Ther. 2006 Dec;319(3):1133-43.
479.48
Formula
C26H23F2N3O4
CAS No.
209984-57-6
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 95 mg/mL (198.1 mM)
Water: <1 mg/mL
Ethanol: 13 mg/mL (27.1 mM)
Solubility (In vivo)
30% PEG400+0.5% Tween80+5% propylene glycol: 30 mg/mL
Synonyms
LSN-411575
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19422389
| In Vitro |
In vitro activity: LY-411575 inhibits γ-secretase which can be assessed by the substrates like amyloid precursor protein (APP) and Notch S3 cleavage. LY-411575, which blocks Notch activation, results in apoptosis in primary and immortalized KS cells. Kinase Assay: 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 manufacturers instructions. Cell Assay: 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. |
|---|---|
| In Vivo | 10 mg/kg oral dose of LY-411575 decreases brain and plasma Aβ40 and -42 dose-dependently. 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. |
| Animal model | TgCRND8 mice model |
| Formulation & Dosage | Formulated as 10 mg/mL solutions in 50% polyethylene glycol, 30% propylene glycol, 10% ethanol and diluted in 0.4% methylcellulose for dosing.; 1-10 mg/kg; oral gavage |
| References | J Biol Chem. 2004 Mar 26;279(13):12876-82; Oncogene. 2005 Sep 22;24(42):6333-44; J Pharmacol Exp Ther. 2006 Dec;319(3):1133-43. |
