Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, United States.
Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot-Watt University, Riccarton, Edinburgh EH14 4AS, U.K.
J Med Chem. 2020 May 28;63(10):5159-5184. doi: 10.1021/acs.jmedchem.9b02094. Epub 2020 May 11.
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 including , , , , , and , which promote EPAC1 guanine nucleotide exchange factor activity . 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, , , , and exhibited improved selectivity toward activation of EPAC1 over EPAC2 in cells. Of these, was 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.
环核苷酸交换蛋白直接激活剂（EPAC）在各种生物学功能中发挥着核心作用，EPAC1 蛋白的激活已显示出在治疗各种人类疾病方面的潜在益处。在此，我们报告了一系列非环核苷酸 EPAC1 激活剂的合成和生化评估。鉴定出了几种有效的 EPAC1 结合物，包括 、 、 、 、 、 ，它们促进 EPAC1 鸟苷核苷酸交换因子活性。这些激动剂还可以在细胞中激活 EPAC1 蛋白，它们对 EPAC 的选择性优于蛋白激酶 A 和 G 蛋白偶联受体。此外， 、 、 、 对细胞中 EPAC1 相对于 EPAC2 的激活表现出改善的选择性。在这些化合物中， 被发现能够强烈抑制白细胞介素 6 激活的信号转导和转录激活因子 3（STAT3）以及随后诱导的促炎血管细胞黏附分子 1（VCAM1）细胞黏附蛋白。因此，这些新型 EPAC1 激活剂可用作阐明 EPAC 功能的有用药理学工具，也是治疗相关人类疾病的有希望的药物先导物。
