| Description |
LY-411575 is a potent γ-secretase inhibitor with IC50 of 0.078 nM/0.082 nM (membrane/cell-based), and also inhibits Notch S3 cleavage with IC50 of 0.39 nM.
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| Related Catalog |
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| Target |
IC50: 0.078 nM (γ-secretase in membrane), 0.082 nM (γ-secretase cell-based), 0.39 nM (Notch S3 cleavage cell-based)[1]
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| In Vitro |
LY-411,575 blocks Notch activation, and results in apoptosis in primary and immortalized KS cells. LY-411,575 (500 μM) induces G2/M growth arrest SLK cells[2]. LY411575 treatment significantly decreases the amounts of intracellular HCV RNA with IC50 of 0.56 ± 0.20 μM and extracellular HCV particles. LY411575 (0-40 nM) alone or in combination with daclatasvir (0-40 pM) decreases supernatant infectious titers in a dose-dependent manner, and is synergistic regarding production of infectious virus. LY411575 (10 µM) treatment impairs ROS production in HCVcc-infected cells[4]. LY411575 significantly attenuates EMT by inhibiting the Notch signaling activation in vitro[5].
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| In Vivo |
LY-411,575 (10 mg/kg) decreases brain and plasma Aβ40 and -42 robustly when chronically administered to TgCRND8 mice[1]. LY411,575 reduces cortical Aβ40 in young transgenic CRND8 mice (ED50 appr 0.6 mg/kg) and produces significant thymus atrophy and intestinal goblet cell hyperplasia at higher doses (>3 mg/kg). The extent of intestinal goblet cell hyperplasia induced by LY411,575 (10 mg/kg) is similar in young and aged mice[3]. LY411575 inhibits mouse proliferative vitreoretinopathy (PVR) formation in vivo[5].
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| Animal Admin |
Mice from the aged cohort (16-26 months old) are either retired breeders or experimentally naive mice. Before dosing begin and for the duration of the study, mice are singly housed with a plastic igloo and nesting material. Mice are sacrificed 2 to 4 h after their final dosing. For oral dosing, LY411,575 and LY-D are formulated as 10 mg/mL solutions and diluted 1:10 with 0.4% methycellulose. In the case of subcutaneous dosing, the 10 mg/mL stock solution is diluted 1:10 with 20% hydroxyl-propyl-β-cyclodextrin. If necessary, serial dilutions are made from the 1 mg/mL solution using the appropriate 1:10 vehicle. The dosing volume is 10 mL/kg. After oral administration of 10 mg/kg LY411,575, inhibition of plasma Aβ is still significant 24, but not 48, h after dosing, so in an effort to maintain continuous γ-secretase inhibition, LY411,575 and LY-D are dosed once per day in all studies.
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| References |
[1]. Wong GT, et al. Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem. 2004 Mar 26;279(13):12876-82. [2]. Curry CL, et al. Gamma secretase inhibitor blocks Notch activation and induces apoptosis in Kaposi's sarcoma tumor cells. Oncogene. 2005 Sep 22;24(42):6333-44. [3]. Hyde LA, et al. Studies to investigate the in vivo therapeutic window of the gamma-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY411,575) in the CRND8 mouse. J Pharmacol Exp Ther. 2006 Dec;319(3):1133-43. [4]. Otoguro T, et al. Inhibitory effect of presenilin inhibitor LY411575 on maturation of hepatitis C virus core protein, production of the viral particle and expression of host proteins involved in pathogenicity. Microbiol Immunol. 2016 Nov;60(11):740-753 [5]. Zhang J, et al. Notch signaling modulates proliferative vitreoretinopathy via regulating retinal pigment epithelial-to-mesenchymal transition. Histochem Cell Biol. 2017 Mar;147(3):367-375.
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