Enzastaurin (LY317615)是一种ATP竞争性、选择性的PKCβ抑制剂，IC50值为6nM。
Cas No.:170364-57-5
Sample solution is provided at 25 µL, 10mM.
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Enzastaurin (LY317615) is an ATP-competitive and selective inhibitor of PKCβ with an IC50 value of 6nM [1]. Enzastaurin reduces phosphor-Cdc25C levels, resulting in G2/M-checkpoint abrogation, and inhibits Akt and GSK3β phosphorylation as well as the secretion of VEGF [2]. Enzastaurin has been widely used to inhibit the phosphorylation level of GSK3β and to restrain the growth of various cancer cells[3].
In vitro, Enzastaurin treatment for 72 hours significantly inhibited the viability of SNU-620 cells and SNU-1 cells, with IC50 values of 3.56µM and 3.78µM, respectively[4]. Treatment with 20µM Enzastaurin for 48 hours significantly induced apoptosis in BCWM.1 cells, accompanied by an increase in the cleavage of caspase-8 and PARP[5]. Treatment with 10µM Enzastaurin for 24 hours significantly inhibited the migration and invasion of A549 cells, and led to a significant downregulation of the HIF1α, VEGFC, and u-PAR genes[6].
In vivo, Enzastaurin treatment via oral administration at a dose of 80mg/kg twice daily for one week significantly enhanced the vascular damage induced by 2Gy radiation in the H460 xenograft mouse model and inhibited tumor growth[7]. Daily subcutaneous injection of a 25mg/kg dose of Enzastaurin for three consecutive days impaired the memory and learning ability of middle-aged rats[8].
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[J]. Cancer research, 2005, 65(16): 7462-7469.
[2] Giovannetti E, Honeywell R, Hanauske A R, et al. Pharmacological aspects of the enzastaurin-pemetrexed combination in non-small cell lung cancer (NSCLC)[J]. Current Drug Targets, 2010, 11(1): 12-28.
[3] Nakajima E, Helfrich B, Chan D, et al. Enzastaurin a protein kinase Cbeta-selective inhibitor, inhibits the growth of SCLC and NSCLC cell lines[J]. Journal of Clinical Oncology, 2006, 24(18_suppl): 13138-13138.
[4] Lee K W, Kim S G, Kim H P, et al. Enzastaurin, a protein kinase Cβ inhibitor, suppresses signaling through the ribosomal S6 kinase and bad pathways and induces apoptosis in human gastric cancer cells[J]. Cancer research, 2008, 68(6): 1916-1926.
[5] Moreau A S, Jia X, Ngo H T, et al. Protein kinase C inhibitor enzastaurin induces in vitro and in vivo antitumor activity in Waldenström macroglobulinemia[J]. Blood, The Journal of the American Society of Hematology, 2007, 109(11): 4964-4972.
[6] Körner A, Mudduluru G, Manegold C, et al. Enzastaurin inhibits invasion and metastasis in lung cancer by diverse molecules[J]. British journal of cancer, 2010, 103(6): 802-811.
[7] Willey C D, Xiao D, Tu T, et al. Enzastaurin (LY317615), a protein kinase C beta selective inhibitor, enhances antiangiogenic effect of radiation[J]. International Journal of Radiation Oncology* Biology* Physics, 2010, 77(5): 1518-1526.
[8] Willeman M N, Mennenga S E, Siniard A L, et al. The PKC-β selective inhibitor, Enzastaurin, impairs memory in middle-aged rats[J]. PloS one, 2018, 13(6): e0198256.
Enzastaurin (LY317615)是一种ATP竞争性、选择性的PKCβ抑制剂，IC50值为6nM[1]。Enzastaurin可降低磷酸化Cdc25C水平，导致G2/M检查点功能丧失，并抑制Akt和GSK3β的磷酸化以及VEGF的分泌[2]。Enzastaurin已被广泛用于抑制GSK3β的磷酸化水平，并抑制多种癌细胞的生长[3]。
在体外，Enzastaurin处理72小时显著抑制了SNU-620细胞和SNU-1细胞的活力，IC50值分别为3.56µM和3.78µM[4]。使用20µM的Enzastaurin处理BCWM.1细胞48小时，显著诱导了细胞凋亡，同时伴随着caspase-8和PARP裂解的增加[5]。使用10µM的Enzastaurin处理A549细胞24小时，显著抑制了细胞的迁移和侵袭，并导致HIF1α、VEGFC和u-PAR基因显著下调[6]。
在体内，在H460异种移植小鼠模型中，每日两次口服80mg/kg剂量的Enzastaurin，持续一周，显著增强了2Gy辐射诱导的血管损伤并抑制了肿瘤生长[7]。连续三天每日皮下注射25mg/kg剂量的Enzastaurin，会损害中年大鼠的记忆和学习能力[8]。
| Kinase experiment [1]: | |
Preparation Method | The inhibition of PKCβII kinase activity by Enzastaurin was determined using a filter plate assay format measuring 33P incorporation into myelin basic protein substrate. Reactions were done in 100μl reaction volumes in 96-well polystyrene plates with final conditions as follows: 90mM HEPES (pH 7.5), 0.001% Triton X-100, 4% DMSO, 5mM MgCl2, 100μM CaCl2, 0.1mg/ml phosphatidylserine, 5μg/ml diacetyl glyerol, 30μM ATP, 0.005μCi/μl 33ATP, 0.25mg/ml myelin basic protein, serial dilutions of Enzastaurin (1, 10, 50, 100, 1000, and 2000nM), and recombinant human PKCβII enzyme (390pM). Reactions were started with enzyme addition, incubated at room temperature for 60 minutes, quenched with 10% H3PO4, transferred to multiscreen anionic phosphocellulose 96-well filter plates, incubated 60 minutes, filtered, and washed with 4 volumes of 0.5% H3PO4 on a vacuum manifold. The scintillation cocktail was added, and the plates were read on a scintillation counter. |
Reaction Conditions | 1, 10, 50, 100, 1000, and 2000nM; 1h |
Applications | Enzastaurin treatment significantly inhibited the kinase activity of PKCβII in a dose-dependent manner. |
| Cell experiment [2]: | |
Cell lines | SNU-620 cells |
Preparation Method | SNU-620 cells were grown in RPMI medium with 10% (v/v) fetal bovine serum (FBS), 100μg/ml streptomycin, and 100U/ml penicillin at 37°C in 5% CO2/atmosphere. SNU-620 cells were seeded on 96-well plates, incubated for 24h, and then then treated with different concentrations of Enzastaurin (0.1, 1, 10, 100, and 1000µM) at 37°C. After 72h, cell viability was measured. |
Reaction Conditions | 0.1, 1, 10, 100, and 1000µM; 72h |
Applications | Enzastaurin treatment significantly reduced the cell viability of SNU-620 cells in a concentration-dependent manner. |
| Animal experiment [3]: | |
Animal models | Athymic nude mice |
Preparation Method | Athymic nude mice (5 weeks old) were housed singly in a standard environment with food and water ad libitum. A suspension of 2×106 H460 cells in 50μl volume was injected subcutaneously into the left hindlimb of mice using a 1-cc syringe with 27.5-gauge needle. Tumors were grown for 1 week until average tumor volume reached 0.28cm3. Treatment groups consisted of vehicle control (5% DMSO) and Enzastaurin (80mg/kg). Each treatment group contained five mice. Enzastaurin at a dose of 80mg/kg was administered by oral gavage twice daily for 7 consecutive days. Tumors were measured three times weekly in three perpendicular dimensions. |
Dosage form | 80mg/kg; twice daily for 7 days; p.o. |
Applications | Enzastaurin treatment significantly inhibited the tumor growth in mice with H460 xenografts. |
References: | |
| 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 |
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.9395 mL | 9.6973 mL | 19.3945 mL |
| 5 mM | 387.9 μL | 1.9395 mL | 3.8789 mL |
| 10 mM | 193.9 μL | 969.7 μL | 1.9395 mL |
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