Enzastaurin (LY317615)
(Synonyms: 恩扎妥林; LY317615) 目录号 : GC11499
An inhibitor of PKC and Akt signaling
Cas No.:170364-57-5
Sample solution is provided at 25 µL, 10mM.
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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.
| Kinase experiment [1]: | |
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Kinase inhibition assays |
The inhibition of PKCβII, PKCα, PKCε, or PKCγ activity by Enzastaurin was determined using a filter plate assay format measuring 33P incorporation into myelin basic protein substrate. Reactions were done in 100 μL reaction volumes in 96-well polystyrene plates with final conditions as follows: 90 mM HEPES (pH 7.5), 0.001% Triton X-100, 4% DMSO, 5 mM MgCl2, 100 μM CaCl2, 0.1 mg/mL phosphatidylserine, 5 μg/mL diacetyl glyerol, 30 μM ATP, 0.005 μCi/μL 33ATP, 0.25 mg/mL myelin basic protein, serial dilutions of enzastaurin (1 ~ 2,000 nM), and recombinant human PKCβII, PKCα, PKCε, or PKCγ enzymes (390, 169, 719, or 128 pM, respectively). Reactions were started by addition of the enzyme and incubated at room temperature for 60 mins. They were then quenched with 10% H3PO4, transferred to multiscreen anionic phosphocellulose 96-well filter plates, incubated for 30 to 90 mins, filtered and washed with 4 volumes of 0.5% H3PO4 on a vacuum manifold. Scintillation cocktail was added and plates were read on a Microbeta scintillation counter. |
| Cell experiment [1]: | |
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Cell lines |
HCT116 colon cancer and U87MG glioblastoma cells |
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Preparation method |
The solubility of this compound in DMSO is > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 °C for several months. |
|
Reacting condition |
4 μM, 48 hrs for both HCT116 colon cancer and U87MG glioblastoma cells; 03 ~ 4 μM for HCT116 colon cancer cells |
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Applications |
In both HCT116 colon cancer and U87MG glioblastoma cells, Enzastaurin induced cell apoptosis. HCT116 colon cancer cells treated with Enzastaurin showed a dose-dependent increase in apoptosis. |
| Animal experiment [1]: | |
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Animal models |
Athymic nude mice bearing HCT116 colon cancer xenografts |
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Dosage form |
75 mg/kg; p.o.; b.i.d., for 21 days |
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Applications |
In mice bearing HCT116 colon cancer xenografts, Enzastaurin significantly suppressed the growth of HCT116 colon carcinoma. Enzastaurin time-dependently inhibited GSK3βSer9 phosphorylation in HCT116 colon cancer xenograft tissues. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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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. | |
| Cas No. | 170364-57-5 | SDF | |
| 别名 | 恩扎妥林; LY317615 | ||
| 化学名 | 3-(1-methylindol-3-yl)-4-[1-[1-(pyridin-2-ylmethyl)piperidin-4-yl]indol-3-yl]pyrrole-2,5-dione | ||
| Canonical SMILES | CN1C=C(C2=CC=CC=C21)C3=C(C(=O)NC3=O)C4=CN(C5=CC=CC=C54)C6CCN(CC6)CC7=CC=CC=N7 | ||
| 分子式 | C32H29N5O2 | 分子量 | 515.61 |
| 溶解度 | ≥ 8.6 mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 1.9395 mL | 9.6973 mL | 19.3945 mL |
| 5 mM | 0.3879 mL | 1.9395 mL | 3.8789 mL |
| 10 mM | 0.1939 mL | 0.9697 mL | 1.9395 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet