LY411575

Catalog No.S2714

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.

Price Stock Quantity  
USD 340 In stock
USD 170 In stock
USD 320 In stock
USD 970 In stock
Bulk Inquiry

Massive Discount Available

Free Overnight Delivery on all orders over $ 500.

LY411575 Chemical Structure

LY411575 Chemical Structure
Molecular Weight: 479.48

Validation & Quality Control

Cited by 1 publications:

Quality Control & MSDS

Gamma-secretase Inhibitors with Unique Features

  • Pan Gamma-secretase Inhibitor

    Semagacestat (LY450139) Aβ42, IC50=10.9 nM; Aβ40, IC50=12.1 nM; Aβ38, IC50=12.0 nM.

  • Gamma-secretase Inhibitor in Clinical Trial

    Semagacestat (LY450139) Phase III for Alzheimer's Disease.

  • Newest Gamma-secretase Inhibitor

    FLI-06 Novel inhibitor of Notch signaling with EC50 of 2.3 μM.

  • Classic Gamma-secretase Inhibitor

    RO4929097 γ-secretase inhibitor with IC50 of 4 nM, inhibiting cellular processing of Aβ40 and Notch with EC50 of 14 nM and 5 nM, respectively. Phase 2.

Product Information

  • Compare Gamma-secretase Inhibitors
    Compare Gamma-secretase Products
  • Research Area

Product Description

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.
Targets γ secretase (membrane-based) [1]
(HEK293 cells expressing either APP or NΔE)
γ secretase (cell-based) [1]
(HEK293 cells expressing either APP or NΔE)
Notch S3 cleavage [1]
(HEK293 cells expressing either APP or NΔE)
IC50 0.078 nM 0.082 nM 0.39 nM
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]
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]
Features

Protocol(Only for Reference)

Kinase Assay:

[1]

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 Assay:

[2]

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.

Animal Study:

[1]

Animal Models TgCRND8 mice model
Formulation LY-411575 is formulated as 10 mg/mL solutions in 50% polyethylene glycol, 30% propylene glycol, 10% ethanol and diluted in 0.4% methylcellulose for dosing.
Dosages 1-10 mg/kg
Administration Orally

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Wong GT, et al, J Biol Chem, 2004, 279(13), 12876-12882.

[2] Curry CL, et al, Oncogene, 2005, 24(42), 6333-6344.

view more

Chemical Information

Download LY411575 SDF
Molecular Weight (MW) 479.48
Formula

C26H23F2N3O4

CAS No. 209984-57-6
Storage 3 years -20℃powder
2 years -80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 95 mg/mL (198.13 mM)
Ethanol 13 mg/mL (27.11 mM)
Water <1 mg/mL
In vivo 30% PEG400+0.5% Tween80+5% propylene glycol 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name Benzeneacetamide, N-[(1S)-2-[[(7S)-6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluoro-α-hydroxy-, (αS)-

Tech Support

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.

Tel: +1-832-582-8158 Ext:3

If you have any other enquiries, please leave a message.

* Indicates a Required Field

Related Gamma-secretase Products

  • PF-03084014 (PF-3084014)

    PF-03084014 (PF-3084014) is a selective gamma-secretase inhibitor with IC50 of 6.2 nM in a cell-free assay. Phase 2.

  • AZD3839

    AZD3839 is a potent and selective BACE1 inhibitor with Ki of 26.1 nM, about 14-fold selectivity over BACE2. Phase 1.

  • Xanthohumol

    Xanthohumol, a prenylated chalcone from hop, inhibits COX-1 and COX-2 activity and shows chemopreventive effects. Phase 1.

  • Avagacestat (BMS-708163)

    Avagacestat (BMS-708163) is a potent, selective, orally bioavailable γ-secretase inhibitor of Aβ40 and Aβ42 with IC50 of 0.3 nM and 0.27 nM, demonstrating a 193-fold selectivity against Notch. Phase 2.

    Features:Appears to be more “notch sparing” than semagacestat (LY450139).

  • RO4929097

    RO4929097 is a γ secretase inhibitor with IC50 of 4 nM in a cell-free assay, inhibiting cellular processing of Aβ40 and Notch with EC50 of 14 nM and 5 nM, respectively. Phase 2.

  • Semagacestat (LY450139)

    Semagacestat (LY450139) is a γ-secretase blocker for Aβ42, Aβ40 and Aβ38 with IC50 of 10.9 nM, 12.1 nM and 12.0 nM, also inhibits Notch signaling with IC50 of 14.1 nM in H4 human glioma cell. Phase 3.

    Features:The best characterized γ-secretase inhibitor that has reached the clinic.

  • DAPT (GSI-IX)

    DAPT (GSI-IX) is a novel γ-secretase inhibitor, which inhibits Aβ production with IC50 of 20 nM in HEK 293 cells.

  • MK-0752

    MK-0752 is a moderately potent γ-secretase inhibitor, which reduces Aβ40 production with IC50 of 5 nM. Phase 1/2.

    Features:A moderately potent γ-secretase inhibitor.

  • YO-01027 (Dibenzazepine)

    YO-01027 (Dibenzazepine) is a dipeptidic γ-secretase inhibitor with IC50 of 2.6 nM and 2.9 nM in cell-free assays for APPL and Notch cleavage, respectively.

  • FLI-06

    FLI-06 is a novel inhibitor of Notch signaling with EC50 of 2.3 μM.

Recently Viewed Items

Tags: buy LY411575 | LY411575 supplier | purchase LY411575 | LY411575 cost | LY411575 manufacturer | order LY411575 | LY411575 distributor
×
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
Contact Us