Exchange proteins directly activated by cAMP (EPACs) are critical cAMP-dependent signaling pathway mediators that play important roles in cancer, diabetes, heart failure, inflammations, infections, neurological disorders and other human diseases. EPAC specific modulators are urgently needed to explore EPAC’s physiological function, mechanism of action and therapeutic applications. On the basis of a previously identified EPAC specific inhibitor hit ESI-09, herein we have designed and synthesized a novel series of 2-substituted phenyl-N-phenyl-2-oxoacetohydrazonoyl cyanides as potent EPAC inhibitors. Compound 31 (ZL0524) has been discovered as the most potent EPAC inhibitor with IC₅₀ values of 3.6 µM and 1.2 µM against EPAC1 and EPAC2, respectively. Molecular docking of 31 onto an active EPAC2 structure predicts that 31 occupies the hydrophobic pocket in cAMP binding domain (CBD) and also opens up new space leading to the solvent region. These findings provide inspirations for discovering next generation of EPAC inhibitors.

由cAMP（EPAC）直接激活的交换蛋白是关键的cAMP依赖性信号通路介质，在癌症，糖尿病，心力衰竭，炎症，感染，神经系统疾病和其他人类疾病中起重要作用。迫切需要EPAC特定的调节剂来探索EPAC的生理功能，作用机理和治疗应用。基于先前鉴定的EPAC特异性抑制剂HES-1-09 ，我们在此设计并合成了一系列新型的2-取代的苯基-N-苯基-2-氧代乙酰肼基酰氰作为有效的EPAC抑制剂。化合物31（ZL0524）被发现是IC ₅₀最有效的EPAC抑制剂分别针对EPAC1和EPAC2的3.6 µM和1.2 µM值。31在活性EPAC2结构上的分子对接预测31在cAMP结合域（CBD）中占据了疏水口袋，并且还开辟了通往溶剂区域的新空间。这些发现为发现下一代EPAC抑制剂提供了启发。