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首页> 外文期刊>Journal of Cardiovascular Development and Disease >The Potential of a Novel Class of EPAC-Selective Agonists to Combat Cardiovascular Inflammation
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The Potential of a Novel Class of EPAC-Selective Agonists to Combat Cardiovascular Inflammation

机译：一类新型的EPAC选择性激动剂与心血管炎症反应的潜力

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The cyclic 3?￠???2,5?￠???2-adenosine monophosphate (cAMP) sensor enzyme, EPAC1, is a candidate drug target in vascular endothelial cells (VECs) due to its ability to attenuate proinflammatory cytokine signalling normally associated with cardiovascular diseases (CVDs), including atherosclerosis. This is through the EPAC1-dependent induction of the suppressor of cytokine signalling gene, SOCS3, which targets inflammatory signalling proteins for ubiquitinylation and destruction by the proteosome. Given this important role for the EPAC1/SOCS3 signalling axis, we have used high throughput screening (HTS) to identify small molecule EPAC1 regulators and have recently isolated the first known non-cyclic nucleotide (NCN) EPAC1 agonist, I942. I942 therefore represents the first in class, isoform selective EPAC1 activator, with the potential to suppress pro-inflammatory cytokine signalling with a reduced risk of side effects associated with general cAMP-elevating agents that activate multiple response pathways. The development of augmented I942 analogues may therefore provide improved research tools to validate EPAC1 as a potential therapeutic target for the treatment of chronic inflammation associated with deadly CVDs.
机译：环状3′→2,5′′→2-腺苷单磷酸（cAMP）传感器酶EPAC1是血管内皮细胞（VEC）的候选药物靶标，因为它通常能够减弱促炎细胞因子信号传导的能力。与心血管疾病（CVD）相关，包括动脉粥样硬化。这是通过EPAC1依赖性诱导的细胞因子信号转导基因SOCS3的抑制剂，该基因靶向炎症信号转导蛋白，以进行蛋白体的泛素化和破坏。鉴于EPAC1 / SOCS3信号转导轴的重要作用，我们已使用高通量筛选（HTS）来识别小分子EPAC1调节剂，并且最近分离出了第一个已知的非环核苷酸（NCN）EPAC1激动剂I942。因此，I942代表同类中的第一个同种型选择性EPAC1激活剂，具有抑制促炎性细胞因子信号转导的潜力，并具有降低与激活多种应答途径的一般cAMP增强剂相关的副作用的风险。因此，增强型I942类似物的开发可能会提供改进的研究工具，以验证EPAC1作为与致命CVD相关的慢性炎症的潜在治疗靶标。

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