Home Proteases Secretase inhibitor - Notch inhibitor - Apoptosis related activator LY411575 For research use only.

LY411575

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.

LY411575 Chemical Structure

LY411575 Chemical Structure

CAS No. 209984-57-6

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LY411575 Related Products

Cell Data

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
CHO Function assay 24 hrs Reduction of human wild type PS1-induced amyloid beta-40 level in CHO cells overexpressing human APP751 after 24 hrs by liquid phase electrochemiluminescence assay relative to control, EC50 = 0.000114 μM. 17573346
HEK293 Function assay Inhibition of gamma secretase in human HEK293 cells assessed as amyloid beta 40 production, EC50 = 0.000119 μM. 17573346
CHO Function assay 24 hrs Reduction of human wild type PS1-induced amyloid beta-42 level in CHO cells overexpressing human APP751 after 24 hrs by liquid phase electrochemiluminescence assay relative to control, EC50 = 0.000135 μM. 17573346
HEK293 Function assay 24 hrs Inhibition of human gamma-secretase expressed in HEK293 cells using Notch1-VP16-Gal4 as substrate after 24 hrs by Bright-Glo luciferase reporter gene assay, IC50 = 0.0003 μM. 29359565
CHO Function assay 24 hrs Reduction of human PS1 delta exon9 mutant-induced amyloid beta-42 level in CHO cells overexpressing human APP751after 24 hrs by liquid phase electrochemiluminescence assay relative to control, EC50 = 0.000352 μM. 17573346
CHO Function assay 24 hrs Reduction of human PS1 delta exon9 mutant-induced amyloid beta-40 level in CHO cells overexpressing human APP751after 24 hrs by liquid phase electrochemiluminescence assay relative to control, EC50 = 0.000358 μM. 17573346
SH-SY5Y Function assay Inhibition of gamma secretase-mediated amyloid beta (1 to 40) production in human SH-SY5Y cells, IC50 = 0.001 μM. 19694467
SH-SY5Y Function assay Displacement of [3H]5-chloro-N-((2S,3R)-5,5,5-trifluoro-1-hydroxy-3-methylpentan-2-yl)thiophene-2-sulfonamide from gamma secretase in human SH-SY5Y cells by competitive binding assay, IC50 = 0.001 μM. 19694467
HEK293 Function assay 24 hrs Inhibition of human SPPL2a expressed in HEK293 cells using GAL4-VP16 fusedTNFalpha (1 to 76)-NTF as substrate after 24 hrs by Bright-Glo luciferase reporter gene assay, IC50 = 0.01 μM. 29359565
U2OS Function assay 24 hrs Inhibition of human SPP expressed in human U2OS cells using EGFP-labeled EnvSigSeq-SEAP as substrate after 24 hrs by Hoechst staining based high content imaging assay, IC50 = 0.05 μM. 29359565
HEK293 Function assay 3 days Modulation of gamma-secretase in HEK293 cells expressing guinea pig Swedish mutant SFV-APP695sw coexpressing DLL4 assessed as inhibition of notch processing in human TE671 cells after 3 days by dual-cell luciferase reporter gene assay, IC50 = 1.2 μM. 24139583
SH-SY5Y Function assay 1 hr Displacement of [3H](S)-5-chloro-N-(3-ethyl-1-hydroxypentan-2-yl)thiophene-2-sulfonamide from gamma secretase in human SH-SY5Y cells after 1 hr 19443228
H4 Function assay 100 nM 16 hrs Inhibition of gamma secretase expressed in human H4 cells expressing BRI-C99 fusion protein assessed as C99 fragment accumulation fragment at 100 nM incubated for 16 hrs in by immunoblot 23181502
H4 Function assay 10 uM 16 hrs Inhibition of gamma secretase expressed in human H4 cells assessed as reduction in C83 levels at 10 uM incubated for 16 hrs by immunoblot 23181502
H4 Function assay 10 uM 16 hrs Inhibition of gamma secretase expressed in human H4 cells assessed as reduction in CTF levels at 10 uM incubated for 16 hrs by immunoblot 23181502
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Biological Activity

Description 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.
Targets
γ secretase [1]
(HEK293 cells expressing either APP or NΔE)		 γ secretase [1]
(HEK293 cells expressing either APP or NΔE)		 Notch S3 cleavage [1]
(HEK293 cells expressing either APP or NΔE)
0.078 nM 0.082 nM 0.39 nM
In vitro
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]
Kinase Assay 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.
Cell Research Cell lines primary and immortalized KS cells
Concentrations 500 μM
Incubation Time 24 hours
Method

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
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]
Animal Research Animal Models TgCRND8 mice model
Dosages 1-10 mg/kg
Administration Orally

Chemical Information & Solubility

Molecular Weight 479.48 Formula

C26H23F2N3O4
CAS No. 209984-57-6 SDF Download LY411575 SDF
Smiles CC(C(=O)NC1C2=CC=CC=C2C3=CC=CC=C3N(C1=O)C)NC(=O)C(C4=CC(=CC(=C4)F)F)O
Storage (From the date of receipt)

In vitro
Batch:

DMSO : 95 mg/mL ( (198.13 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : 13 mg/mL

Water : Insoluble


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Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Frequently Asked Questions

Question 1:
Does this inhibitor act on beta-secretase?.

Answer:
LY411575 has been reported to inhibit gamma-secretase, currently, there is no publication reporting its inhibition on beta-secreatse.

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