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.

CAS No. 209984-57-6

サイズ	価格(税別)	在庫状況
10mM (1mL in DMSO)	JPY 40500	国内在庫あり
5mg	JPY 25500	国内在庫あり
50mg	JPY 118500	国内在庫あり
1g	JPY 448500	国内在庫なし(納期7~10日)

代表番号: 045-509-1970\|電子メール：[email protected] よく尋ねられる質問

文献中Selleckの製品使用例（35）

製品安全説明書

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LY411575関連製品

関連ターゲット	gamma-secretase	もっと見る
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関連化合物ライブラリー	FDA-approved Drug Library Natural Product Library Bioactive Compound Library-I Protease Inhibitor Library Ubiquitination Compound Library	もっと見る

Secretase阻害剤の選択性比較

Cell Data

Cell Lines	Assay Type	Concentration	Incubation Time	活性情報	PMID
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
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
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
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 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
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		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
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
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
HEK293	Function assay			Inhibition of gamma secretase in human HEK293 cells assessed as amyloid beta 40 production, EC50 = 0.000119 μM.	17573346
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生物活性

製品説明

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
Kinase Assay	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.
細胞実験	細胞株	primary and immortalized KS cells
	濃度	500 μM
	反応時間	24 hours
	実験の流れ	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]
動物実験	動物モデル	TgCRND8 mice model
	投与量	1-10 mg/kg
	投与経路	Orally

参考
[1] Wong GT, et al, J Biol Chem, 2004, 279(13), 12876-12882. [2] Curry CL, et al, Oncogene, 2005, 24(42), 6333-6344. [2] Hyde LA, et al, J Pharmacol Exp Ther, 2006, 319(3), 1133-1143.

参考

化学情報

分子量	479.48	化学式	C₂₆H₂₃F₂N₃O₄
CAS No.	209984-57-6	SDF	Download LY411575 SDFをダウンロードする
Smiles	CC(C(=O)NC1C2=CC=CC=C2C3=CC=CC=C3N(C1=O)C)NC(=O)C(C4=CC(=CC(=C4)F)F)O
保管	3年-20°C粉	溶液の保管冷凍と解凍の繰り返しを避けるため小分けにしてください	1年-80°Cin solvent
保管	3年-20°C粉	溶液の保管冷凍と解凍の繰り返しを避けるため小分けにしてください	1个月-20°Cin solvent

In vitro
Batch:

DMSO : 95 mg/mL ( (198.13 mM)；吸湿したDMSOは溶解度を減少させます。新しいDMSOをご使用ください。)

Ethanol : 13 mg/mL

Water : Insoluble

モル濃度計算器

in vivo Batch: Add solvents to the product individually and in order.					投与溶液組成計算機
	Clear solution	5% DMSO 1 95% Corn oil	0.65mg/ml	Taking the 1 mL working solution as an example, add 50 μL of 13 mg/ml clear DMSO stock solution to 950 μL of corn oil and mix evenly. The mixed solution should be used immediately for optimal results.	投与溶液組成計算機
Clear solution	30%PEG400 1 0.5%Tween80 2 5%propylene glycol	30.0mg/ml	Taking the 1 mL working solution as an example, add 300 μL of 100 mg/ml clarified PEG400 stock solution to 5 μL of Tween80, mix evenly to clarify it; add 50 μL Propylene glycol to the above system, mix evenly to clarify it; then continue to add 645 μL ddH2O to adjust the volume. to 1 mL. The mixed solution should be used immediately for optimal results.
Clear solution	5%DMSO 1 40%PEG300 2 5%Tween80 3 50%ddH2O	5.0mg/ml	Taking the 1 mL working solution as an example, add 50 μL of 100 mg/ml clarified DMSO stock solution to 400 μL of PEG300, mix evenly to clarify it; add 50 μL of Tween80 to the above system, mix evenly to clarify; then continue to add 500 μL of ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results.

実験計算

モル濃度計算器

質量	濃度	体積	分子量
=	×	×

希釈計算器分子量計算器

投与溶液組成計算機(クリア溶液)

ステップ１：実験データを入力してください。（実験操作によるロスを考慮し、動物数を1匹分多くして計算・調製することを推奨します）

投与量 mg/kg 動物平均体重 g 投与体積（動物毎）μL 動物数匹

ステップ２：投与溶媒の組成を入力してください。（ロット毎に適した溶解組成が異なる場合があります。詳細については弊社までお問い合わせください）

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

計算結果：

投与溶媒濃度： mg/ml;

DMSOストック溶液調製方法： mg 試薬を μL DMSOに溶解する（濃度 mg/mL, 注：濃度が当該ロットのDMSO溶解度を超える場合はご連絡ください。 )

投与溶媒調製方法：Take μL DMSOストック溶液に μL PEG300，を加え、完全溶解後μL Tween 80，を加えて完全溶解させた後 μL ddH₂O，を加え完全に溶解させます。

投与溶媒調製方法：μL DMSOストック溶液に μL Corn oil，を加え、完全溶解。

注意：１.ストック溶液に沈殿、混濁などがないことをご確認ください；
２.順番通りに溶剤を加えてください。次のステップに進む前に溶液に沈殿、混濁などがないことを確認してから加えてください。ボルテックス、ソニケーション、水浴加熱など物理的な方法で溶解を早めることは可能です。

C1=C0/X	C1:	LOG(C1):
C2=C1/X	C2:	LOG(C2):
C3=C2/X	C3:	LOG(C3):
C4=C3/X	C4:	LOG(C4):
C5=C4/X	C5:	LOG(C5):
C6=C5/X	C6:	LOG(C6):
C7=C6/X	C7:	LOG(C7):
C8=C7/X	C8:	LOG(C8):