LY411575 209984-57-6

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Molecular Weight:

479.48 LY411575 is a potent γ-secretase inhibitor with IC50 of 0.078 nM/0.082 nM (membrane/cell-based), also inhibits Notch clevage with IC50 of 0.39 nM.

Biological 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.


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.




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.

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Product Categories : Proteases > Gamma-secretase Inhibitor