ESI-09
目录号 : GC11877
ESI-09是一种新型且具有细胞渗透性和特异性的cAMP直接激活交换蛋白（EPAC）抑制剂，对EPAC1和EPAC2的IC50值分别为3.2和1.4μM。
Cas No.:263707-16-0
Sample solution is provided at 25 µL, 10mM.
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ESI-09 is a novel, cell-permeable, and specific inhibitor of the exchange protein directly activated by cAMP (EPAC), exhibiting IC50 values of 3.2μM and 1.4μM for EPAC1 and EPAC2, respectively[1]. ESI-09 functions by blocking the guanine nucleotide exchange factor (GEF) activity of EPAC, thereby influencing downstream processes such as Akt phosphorylation and pancreatic cancer cell migration[2]. ESI-09 is commonly used to investigate the roles of EPAC proteins in cellular processes and disease models, such as pancreatic cancer and breast cancer[3].
In vitro, treatment of human non-small cell lung cancer A549 cell line with ESI-09 (2μM) for 48h in a glucose-free medium significantly reduced intracellular ATP content, increased the ADP/ATP ratio, and induced both apoptosis and necrosis[4]. Treatment of pancreatic cancer PANC-1 cells with ESI-09 (1-10μM) alone for 48h inhibited cell viability in a dose-dependent manner. The combination of 10mM LiCl and 10μM ESI-09 exhibited a synergistic effect, resulting in a significantly enhanced inhibition of PANC-1 cell viability[5]. Treatment of hippocampal neurons with ESI-09 (15μM) for 48h significantly reduced the percentage of polarized neurons and shortened axon length[6].
In vivo, ESI-09 (2mg/kg/day or 10mg/kg/day) administered via intraperitoneal injection to mice bearing A549 tumor xenografts for 21 days significantly inhibited tumor growth from day 16 onwards and reduced plasma carcinoembryonic antigen (CEA) levels[4]. Pretreatment of wild-type C57BL/6 mice with ESI-09 (10mg/kg/day) via intraperitoneal injection for 5 days, followed by intravenous inoculation with Rickettsia australis and continued ESI-09 administration for another 7 days, significantly alleviated disease severity and improved survival rate[7].
References:
[1] ALMAHARIQ M, TSALKOVA T, MEI F C, et al. A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion[J]. Molecular Pharmacology, 2013, 83(1): 122-128.
[2] AHMED A, BOULTON S, SHAO H, et al. Recent advances in EPAC-targeted therapies: a biophysical perspective[J]. Cells, 2019, 8(11): 1462.
[3] PARNELL E, PALMER T M, YARWOOD S J. The future of EPAC-targeted therapies: agonism versus antagonism[J]. Trends in Pharmacological Sciences, 2015, 36(4): 203-214.
[4] MAEDA Y, KIKUCHI R, KAWAGOE J, et al. Anti-cancer strategy targeting the energy metabolism of tumor cells surviving a low-nutrient acidic microenvironment[J]. Molecular Metabolism, 2020, 42: 101093.
[5] WANG X, LUO C, CHENG X, et al. Lithium and an EPAC-specific inhibitor ESI-09 synergistically suppress pancreatic cancer cell proliferation and survival[J]. Acta Biochimica et Biophysica Sinica, 2017, 49(7): 573-580.
[6] MUÑOZ-LLANCAO P, HENRÍQUEZ D R, WILSON C, et al. Exchange protein directly activated by cAMP (EPAC) regulates neuronal polarization through Rap1B[J]. Journal of Neuroscience, 2015, 35(32): 11315-11329.
[7] GONG B, SHELITE T, MEI F C, et al. Exchange protein directly activated by cAMP plays a critical role in bacterial invasion during fatal rickettsioses[J]. Proceedings of the National Academy of Sciences of the United States of America, 2013, 110(48): 19615-19620.
ESI-09是一种新型且具有细胞渗透性和特异性的cAMP直接激活交换蛋白（EPAC）抑制剂，对EPAC1和EPAC2的IC50值分别为3.2和1.4μM[1]。ESI-09通过阻断EPAC的鸟嘌呤核苷酸交换因子（GEF）活性发挥作用，可影响Akt磷酸化和胰腺癌细胞迁移等下游过程[2]。ESI-09通常用于研究EPAC蛋白在细胞过程和疾病模型（如胰腺癌和乳腺癌）中的作用[3]。
在体外，ESI-09（2μM）处理非小细胞肺癌A549细胞系48h，在无葡萄糖培养基中可显著降低细胞内ATP含量、提高ADP/ATP比率，并诱导细胞凋亡和坏死[4]。ESI-09（1-10μM）单独处理胰腺癌PANC-1细胞48h，可剂量依赖性地抑制细胞活力。10mM LiCl 和10μM ESI-09 联合使用对 PANC-1 细胞的抑制作用显著增强，在抑制细胞活力方面有很强的协同作用[5]。ESI-09（15μM）处理海马神经元48h，显著降低了极化神经元百分比并缩短了轴突长度[6]。
在体内，ESI-09（2mg/kg/day或10mg/kg/day）通过腹腔注射治疗携带A549肿瘤异种移的小鼠21天，从第16天起显著抑制肿瘤生长，并降低了血浆癌胚抗原（CEA）水平[4]。ESI-09（10mg/kg/day）通过腹腔注射预处理野生型C57BL/6小鼠5天，后静脉接种感染Rickettsia australis，ESI-09继续给药7天，能显著减轻疾病严重程度并提高存活率[7]。
| Cell experiment [1]: | |
Cell lines | PANC-1 cells (pancreatic ductal adanocacinoma cell lines) |
Preparation Method | PANC-1 cells were suspended and seeded in the opaque-walled multiple-well plates (5000 cells/100μl/well) and cultured overnight. Cells were treated with ESI-09 (1-10μM) alone, or treated with LiCl (1-10mM) + ESI-09 (1-10μM) in combinations for 48h. A total of 100μl of CellTiter-Glo® 2.0 reagent was added to each well and incubated for 10min to determine cell viability. The luminescence intensity was recorded using a microplate reader. |
Reaction Conditions | 1, 3, 5, and 10μM; 48h |
Applications | ESI-09 inhibited PANC-1 cell viability dose-dependently. Combination of LiCl and ESI-09 showed a significantly larger inhibitory effect toward PANC-1 cells, compared with LiCl or ESI-09 alone, a strong synergism between LiCl and ESI-09 in inhibiting PANC-1 cell viability. |
| Animal experiment [2]: | |
Animal models | BALB/c-nu (nu/nu) mice bearing A549 cell xenografts |
Preparation Method | To generate tumor xenografts, A549 cells (5 × 106 cells) in 100μl of phosphate-buffered saline were injected into the subcutaneous flanks of nude mice. When the tumor volumes reached an average of approximately 100-150mm3, mice were treated with a monotherapy with ESI-09 (2mg/kg/day or 10mg/kg/day; 21 days; i.p.). At the end of the treatment period, blood samples were obtained by vena cava puncture under terminal anesthesia and the tumors were harvested and weighed. Plasma levels of CEA were measured using a human CEA ELISA kit. |
Dosage form | 2mg/kg/day or 10mg/kg/day; 21 days; i.p. |
Applications | The monotherapy with ESI-09 at 2mg/kg/day or 10mg/kg/day significantly inhibited tumor growth by day 16. The plasma CEA levels were also significantly decreased in the mice treated with ESI-09 alone. |
References: | |
| Cas No. | 263707-16-0 | SDF | |
| 化学名 | (1E)-2-(5-tert-butyl-1,2-oxazol-3-yl)-N-(3-chloroanilino)-2-oxoethanimidoyl cyanide | ||
| Canonical SMILES | CC(C)(C)C1=CC(=NO1)C(=O)C(=NNC2=CC(=CC=C2)Cl)C#N | ||
| 分子式 | C16H15ClN4O2 | 分子量 | 330.77 |
| 溶解度 | ≥ 33.1mg/mL in DMSO | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.0232 mL | 15.1162 mL | 30.2325 mL |
| 5 mM | 604.6 μL | 3.0232 mL | 6.0465 mL |
| 10 mM | 302.3 μL | 1.5116 mL | 3.0232 mL |
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