The Potential of a Novel Class of EPAC-Selective Agonists to Combat Cardiovascular Inflammation.
The Potential of a Novel Class of EPAC-Selective Agonists to Combat Cardiovascular Inflammation.
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DOI：
10.3390/jcdd4040022
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发表时间：
2017-12-05
影响因子：
2.4
通讯作者：
Yarwood SJ
中科院分区：
文献类型：
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作者：
Barker G;Parnell E;van Basten B;Buist H;Adams DR;Yarwood SJ
环3′，5 ′-腺苷一磷酸（cAMP）传感酶EPAC 1是血管内皮细胞（VEC）中的候选药物靶标，因为其能够减弱通常与心血管疾病（CVD）（包括动脉粥样硬化）相关的促炎细胞因子信号传导。这是通过细胞因子信号传导基因SOCS 3的抑制因子的EPAC 1依赖性诱导，SOCS 3靶向炎症信号传导蛋白，用于蛋白体的泛素化和破坏。鉴于EPAC 1/SOCS 3信号轴的重要作用，我们使用高通量筛选（HTS）来鉴定小分子EPAC 1调节剂，最近分离出第一个已知的非环核苷酸（NCN）EPAC 1激动剂I942。因此，I942代表了同类中的第一种亚型选择性EPAC 1激活剂，具有抑制促炎细胞因子信号传导的潜力，同时降低了与激活多种反应途径的一般cAMP升高剂相关的副作用风险。因此，增强的I942类似物的开发可以提供改进的研究工具，以验证EPAC 1作为治疗与致命CVD相关的慢性炎症的潜在治疗靶点。
The cyclic 3′,5′-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.