Synthesis and Biochemical Evaluation of Noncyclic Nucleotide Exchange Proteins Directly Activated by cAMP 1 (EPAC1) Regulators.
Synthesis and Biochemical Evaluation of Noncyclic Nucleotide Exchange Proteins Directly Activated by cAMP 1 (EPAC1) Regulators.
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由 cAMP 1 (EPAC1) 调节剂直接激活的非环状核苷酸交换蛋白的合成和生化评价。
DOI：
10.1021/acs.jmedchem.9b02094
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发表时间：
2020
影响因子：
7.3
通讯作者：
Wang P
中科院分区：
文献类型：
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作者：
Wang P
由cAMP直接激活的交换蛋白（EPAC）在各种生物学功能中起着核心作用，并且EPAC 1蛋白的激活已经显示出治疗各种人类疾病的潜在益处。在此，我们报告了一系列非环核苷酸EPAC 1激活剂的合成和生化评价。在体外实验中发现了几种有效的EPAC 1结合剂，包括25 g、25 q、25 n、25 u、25 e和25 f，它们可以促进EPAC 1鸟嘌呤核苷酸交换因子的活性。这些激动剂还可以激活细胞中的EPAC 1蛋白，在细胞中它们对EPAC表现出优于蛋白激酶A和G蛋白偶联受体的优异选择性。此外，25 e、25 f、25 n和25 u在细胞中对EPAC 1的活化的选择性优于EPAC 2。其中，发现25 u强烈抑制IL-6激活的信号转导子和转录激活子3（STAT 3）以及随后的促炎性血管细胞粘附分子1（VCAM 1）细胞粘附蛋白的诱导。因此，这些新的EPAC 1激活剂可以作为有用的药理学工具，用于阐明EPAC功能和有前途的药物线索，用于治疗相关的人类疾病。
Exchange proteins directly activated by cAMP (EPAC) play a central role in various biological functions, and activation of the EPAC1 protein has shown potential benefits for the treatment of various human diseases. Herein, we report the synthesis and biochemical evaluation of a series of noncyclic nucleotide EPAC1 activators. Several potent EPAC1 binders were identified including25g,25q,25n,25u,25e, and25f, which promote EPAC1 guanine nucleotide exchange factor activityin vitro. These agonists can also activate EPAC1 protein in cells, where they exhibit excellent selectivity toward EPAC over protein kinase A and G protein-coupled receptors. Moreover,25e,25f,25n, and25uexhibited improved selectivity toward activation of EPAC1 over EPAC2 in cells. Of these,25uwas found to robustly inhibit IL-6-activated signal transducer and activator of transcription 3 (STAT3) and subsequent induction of the pro-inflammatory vascular cell adhesion molecule 1 (VCAM1) cell-adhesion protein. These novel EPAC1 activators may therefore act as useful pharmacological tools for elucidation of EPAC function and promising drug leads for the treatment of relevant human diseases.