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]。