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LY-411575

现货
Catalog No.
A4019
γ分泌酶抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,300.00
现货
5mg
¥ 720.00
现货
10mg
¥ 1,300.00
现货
50mg
¥ 3,900.00
现货
100mg
¥ 5,700.00
现货

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Background

LY-411575 is a potent  inhibitor of γ-secretase with IC50 value of 0.078 nM in membrane assay.[1]
γ-Secertase is one of intramenbrane-cleaving aspartyl protease which cleaves many type-I membrane proteins and many of them have important biological functions. γ-Secretase is a multi-subunit protease and it contains presenilin, nicastrin, APH-1(Anterior Pharynx- defective 1) and PEN-2. Presenilin contains Asp258 and Asp385 embedded in the sixth and seventh transmembrane domain and forms the active site. The feature of being a membrane integrated protease complex makes it difficult to be purified as well as studying its mechanism.γ-secretase is responsible for the generation Aβfrom the amyloid precursor protein.γ-Secertase has been considered as an important drug target for Alzheimer's disease.γ-Secertase also is responsible for Notch processing which is related to cancer such as leukemia.[2]
LY-411,575 significantly inhibits theγ-secretase activity in vitro. LY-411,575 inhibits the production of Aβproduction with IC50 value of 0.078 nM in membrane-assay and 0.082 nM in cell-basedγ-secretase assays, respectively. LY-411,575 also affects the Notch pathway by inhibiting Notch S3 cleavage with IC50 value of 0.39 nM.[1] LY-411,575 treatment also significantly inhibited the Notch pathway by inhibiting the γ-secretase activity luciferase activity in primary KS cells. LY-411,575 also induced the apoptosis though Notch pathway inhibition in primary and immortalized Kaposi's sarcoma (KS) tumor cells.[2]
LY-411,575 decreases the levels of brain and plasma Aβ40 and -42 at 10 mg/kg oral doses.[1] LY-411,575 also decreases cortical Aβ40 levels in transgenic CRND8 mice with ED50 ≈ 0.6 mg/kg. LY-411,575 also induced significantly intestinal goblet cell hyperplasia and thymus atrophy by inhibiting Notch signaling pathway at higher doses in vivo.[3]
References:
1.Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, Engstrom L, Pinzon-Ortiz M, Fine JS, Lee HJ 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, 279(13):12876-12882.
2.Curry CL, Reed LL, Golde TE, Miele L, Nickoloff BJ, Foreman KE: Gamma secretase inhibitor blocks Notch activation and induces apoptosis in Kaposi's sarcoma tumor cells. Oncogene 2005, 24(42):6333-6344.
3.Hyde LA, McHugh NA, Chen J, Zhang Q, Manfra D, Nomeir AA, Josien H, Bara T, Clader JW, Zhang L 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-di hydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY411,575) in the CRND8 mouse. J Pharmacol Exp Ther 2006, 319(3):1133-1143.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt479.48
Cas No.209984-57-6
FormulaC26H23F2N3O4
Solubility≥23.85 mg/mL in DMSO, ≥98.4 mg/mL in EtOH with ultrasonic, <2.54 mg/mL in H2O
Chemical Name(2S)-2-[[(2S)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-N-[(7S)-5-methyl-6-oxo-7H-benzo[d][1]benzazepin-7-yl]propanamide
SDFDownload SDF
Canonical SMILESCC(C(=O)NC1C2=CC=CC=C2C3=CC=CC=C3N(C1=O)C)NC(=O)C(C4=CC(=CC(=C4)F)F)O
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

激酶实验 [1]:

抑制活性

制备表达APP的HEK293细胞的细胞膜,测定γ-分泌酶活性。用不同浓度的LY-411、575处理表达APP或N E的完整HEK293细胞,37℃4小时。在表达N E的情况下,裂解细胞,在4-12%NuPAGE凝胶上分离细胞裂解物,使用切割位点特异性抗体通过蛋白质印迹检测加工的NICD片段。使用FluorChem通过斑密度计量分析来定量NICD的抑制作用。在表达APP的细胞中,收集条件培养基,以10,000×g离心5分钟以去除细胞碎片,在测定Aβ水平之前储存在-20℃。在基于HEK293膜和细胞的测定中Aβ40和-42的产生,以及来自TgCRND8小鼠的血浆Aβ40和皮质Aβ40,在没有预处理的情况下使用基于电化学发光检测的免疫测定分析。通过酶联免疫吸附测定测量血浆Aβ42。使用市售的酶联免疫吸附测定试剂盒测定皮质Aβ42。

细胞实验 [1]:

细胞系

表达Swedish 和London突变人APP或表达N E的HEK293细胞

溶解方法

该化合物在DMSO中的溶解度大于10 mM。若配制更高浓度的溶液,一般步骤如下:请将试管置于37℃加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20℃可放置数月

反应条件

4 h

实验结果

在表达人APP或N E的HEK293细胞中,LY-411,575分别抑制Aβ40和NICD的生成,IC50值分别为0.082和0.39 nM。

动物实验[1]:

动物模型

六周龄雌性TgCRND8或雄性C57BL/6小鼠。

剂量

1-10 mg/kg,口服,每天一次,持续5或15 天

实验结果

在50%聚乙二醇、30%丙二醇、10%乙醇中配制10 mg/ml溶液,使用0.4%甲基纤维素稀释用于给药。

注意事项

在TgCRND8小鼠中,LY-411,575降低脑和血浆Aβ40和Aβ42。LY-411,575(10 mg/kg)使小鼠体重减轻2g。LY-411,575诱导胸腺皮质区的显著萎缩,并减少胸腺细胞的数量。

动物模型

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同。这是由实验系统的误差引起的,属于正常现象。

References:

[1]. Wong GT, Manfra D, Poulet FM, 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 BiolChem, 2004, 279(13): 12876-12882.

生物活性

描述 LY411575是一种有效的γ-secretase抑制剂,IC50值为0.078 nM/0.082 nM(基于膜/细胞)。
靶点 γ-secretase Notch S3 cleavage        
IC50 0.078 nM (membrane-based) 0.082 nM (cell-based) 0.39 nM        

质量控制

化学结构

LY-411575