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Enzastaurin (LY317615)

现货
Catalog No.
A1670
PKCβ抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 700.00
现货
5mg
¥ 500.00
现货
25mg
¥ 1,200.00
现货
100mg
¥ 3,600.00
现货

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Background

Enzastaurin is an ATP-competitive, selective oral inhibitor of protein kinase Cβ with IC50 value of 6 nM [1].

Protein kinase C (PKC) is a family of serine-threonine protein kinases that have been proved to play critical roles in the formation and progression of tumor cells. The PKCβ is especially found to contribute to the growth and proliferation of tumors such as diffuse large B-cell lymphoma, multiple myeloma and chronic lymphoid leukemia. The selective PKCβ inhibitor enzastaurin was found to have antiangiogenic activity in tumor model as well as suppress tumor proliferation and induce apoptosis. Besides that, enzastaurin showed the inhibitory effects on phosphorylation of ribosomal protein S6, GSK3β and AKT which are in pathways influenced by PKC. Due to these, enzastaurin was developed as a therapy for cancer [1 and 2].

Enzastaurin at low concentration suppressed cell proliferation of various tumor cells including colon carcinoma (HCT-116), glioblastoma (U87MG), non–small cell lung cancer (A549), melanoma (M14), ovarian cancer (OVCAR-3), breast cancer (MCF-7), leukemia (K562), prostate cancer (PC-3), renal cancer (CAKI-1) and central nervous system cancer (U251). Enzastaurin induced apoptosis of tumor cells at low concentration in a range of 1 to 4 μM and the apoptosis was proved to be caspase-independent. In addition, enzastaurin suppressed the phosphorylation ofGSK3βSer9, ribosomal protein S6Ser240/244 and AKTThr308 time-dependently in tumor cells and affected these pathways [1 and 3].

In mice models, oral administration of enzastaurin at a dose of 75 mg/kg resulted in significant proliferation inhibition of U87MG glioblastoma or HCT116 coloncarcinoma xenografts. In mice bearing human walden strommacro globulinemia xenografts, administration of enzastaurin at dose of 80 mg/kg significantly reduced tumor growth of WM and increased survival [1 and 2].

Reference:
[1] Graff J R, McNulty A M, Hanna K R, et al.  The protein kinase Cβ–selective inhibitor, enzastaurin (LY317615.HCl), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts. Cancer Research, 2005, 65(16): 7462-7469.
[2] Moreau A S, Jia X, Ngo H T, et al.  Protein kinase C inhibitor enzastaurin induces in vitro and in vivo antitumor activity in Waldenstr mmacroglobulinemia. Blood, 2007, 109(11): 4964-4972.
[3] Rizvi M A, Ghias K, Davies K M, et al.  Enzastaurin (LY317615), a protein kinase Cβ inhibitor, inhibits the AKT pathway and induces apoptosis in multiple myeloma cell lines. Molecular cancer therapeutics, 2006, 5(7): 1783-1789.

文献引用

1. Huichalaf CH, Al-Ramahi I, Pet al."Cross-species genetic screens to identify kinase targets for APP reduction in Alzheimer's disease." Hum Mol Genet. 2019 Feb 12. PMID:30753434
2. Piano I, Baba K, et al. "Heteromeric MT(1)/MT(2) melatonin receptors modulate the scotopic electroretinogram via PKCζ in mice." Exp Eye Res. 2018 Jul 27;177:50-54. PMID:30059666

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt515.61
Cas No.170364-57-5
FormulaC32H29N5O2
Solubility≥8.6 mg/mL in DMSO, <2.68 mg/mL in H2O, <2.57 mg/mL in EtOH
Chemical Name3-(1-methylindol-3-yl)-4-[1-[1-(pyridin-2-ylmethyl)piperidin-4-yl]indol-3-yl]pyrrole-2,5-dione
SDFDownload SDF
Canonical SMILESCN1C=C(C2=CC=CC=C21)C3=C(C(=O)NC3=O)C4=CN(C5=CC=CC=C54)C6CCN(CC6)CC7=CC=CC=N7
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]:

激酶抑制实验

使用滤板法测定整合到髓鞘碱性蛋白底物的33P量,从而测定Enzastaurin对PKCβII、 PKCα、PKCε或PKCγ的抑制活性。在96孔板上,反应体积为100 μL。反应体系包括90 mM HEPES (pH 7.5)、0.001% Triton X-100、4% DMSO、5 mM MgCl2, 100 μM CaCl2、0.1 mg/mL磷脂酰丝氨酸、5 μg/mL二乙酰甘油、30 μM ATP、0.005 μCi/μL 33ATP、0.25 mg/mL髓鞘碱性蛋白、Enzastaurin的连续稀释溶液 (1 ~ 2,000 nM) 以及重组人类PKCβII、PKCα、PKCε或 PKCγ酶(分别为390、169,、719或128 pM)。加入酶开始反应,反应于室温下温育60分钟。加入10% H3PO4终止反应,将反应体系转移到多屏阴离子磷酸纤维素96孔滤板上,将其孵育30 ~ 90分钟,过滤,在真空歧管中用4倍体积的0.5% H3PO4冲洗。加入闪烁混合物,将板置于Microbeta闪烁计数器上读数。

细胞实验 [1]:

细胞系

HCT116结肠癌和U87MG胶质母细胞瘤细胞

制备方法

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 °C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 °C可放置数月。

反应条件

4 μM,48小时(HCT116结肠癌和U87MG胶质母细胞瘤细胞);03 ~ 4 μM(HCT116结肠癌细胞)

实验结果

在HCT116结肠癌和U87MG胶质母细胞瘤细胞中,Enzastaurin诱导细胞凋亡。Enzastaurin呈剂量依赖性地增加HCT116结肠癌细胞凋亡。

动物实验 [1]:

动物模型

携带HCT116结肠癌异种移植物的无胸腺裸鼠

给药剂量

75 mg/kg;口服给药;每日2次,持续21日

实验结果

在携带HCT116结肠癌异种移植物的小鼠中,Enzastaurin显著抑制HCT116结肠癌生长。 Enzastaurin呈时间依赖性地抑制HCT116结肠癌异种移植组织中的GSK3βSer9磷酸化。

注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

[1]. Graff J R, McNulty A M, Hanna K R, et al. The protein kinase Cβ–selective inhibitor, enzastaurin (LY317615.HCl), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts. Cancer Research, 2005, 65(16): 7462-7469.

生物活性

描述 Enzastaurin (LY317615)是一种有效的和选择性的PKCβ抑制剂,IC50值为6 nM。
靶点 PKCβ PKCα PKCγ PKCε    
IC50 6 nM 39 nM 83 nM 110 nM    

质量控制

化学结构

Enzastaurin (LY317615)

相关生物数据

Enzastaurin (LY317615)

相关生物数据

Enzastaurin (LY317615)

相关生物数据

Enzastaurin (LY317615)

相关生物数据

Enzastaurin (LY317615)