biological activity | LY411575 is an effective γ-secretase inhibitor. IC50 is 0.078 nM/0.082 nM (based on membrane/cell) in HEK293 cells expressing APP or NΔE, which also inhibits Notch division and IC50 is 0.39 nM. LY411575 can induce apoptosis. |
target | TargetValue gamma secretase (membrane-based) (hek293 cells expressing either app or nΔ e) 0.078 nmγ secretase (hek293 cells expressing either app or nΔ e) 0.082 nmnotch S3 cleavage (hek293 cells expressing either app or nΔ e) 0.39 nm |
|
Target | Value |
γ secretase (membrane-based)
(HEK293 cells expressing either APP or NΔE)
| 0.078 nM |
γ secretase (cell-based)
(HEK293 cells expressing either APP or NΔE)
| 0.082 nM |
Notch S3 cleavage
(HEK293 cells expressing either APP or NΔE)
| 0.39 nM |
in vitro study | LY-411575 inhibit γ-secretion, which can be evaluated by substrate amyloid precursor protein (APP) and Notch S3 cleavage. In primary and immortalized KS cells, LY-411575 blocked Notch activation, resulting in apoptosis. |
in vivo study | 10 mg/kg oral dose LY-411575 dose-dependent reduction of brain and plasma Aβ40 and Aβ42. In young (preplaque) transgenic CRND8 mice, the cortical layer Aβ40(ED50 ≈ 0.6 mg/kg) was LY-411575 reduced, and at higher doses (>3 mg/kg), significant thymus atrophy and intestinal goblet cell proliferation were produced. In young and old CRND8 mice, oral and subcutaneous administration, the therapeutic window is similar. Thymus and intestinal side effects are reversible after a 2-week clearance period. Treatment with 1 mg/kg LY411575 for 3 weeks reduced 69% cortical Aβ40 without inducing intestinal effects, although previously unreported changes in coat color would be observed. |