NEDD8 activating enzyme (NAE) plays an important role in regulating intracellular proteins with key parts in a broad array of cellular functions. On the basis of previously work, a series of 2H-chromen-2-one based NAE inhibitors were designed and synthesized. Through enzyme-based and cell-based assays, LP0040 was identified as a non-nucleoside NAE/UAE dual inhibitor. It could inhibit NAE/UAE activities and downregulated degradations of related substrates in AGS cells, promoting apoptosis in low micromole concentrations. LP0040 possessed anti-proliferation activities with IC₅₀ values of 0.76–3.29 μM against multiple human cancer lines and had synergistic effect with bortezomib. Thus LP0040 represented valuable starting points for future development of NAE/UAE dual inhibitors.

NEDD8活化酶（NAE）在调节细胞功能广泛的关键部位的细胞内蛋白质中起着重要作用。在以前的工作的基础上，设计和合成了一系列基于2H-铬-2--2-酮的NAE抑制剂。通过基于酶和基于细胞的测定，LP0040被鉴定为非核苷NAE / UAE双重抑制剂。它可以抑制NAE / UAE活性，并下调AGS细胞中相关底物的降解，从而在低微摩尔浓度下促进细胞凋亡。LP0040具有抗增殖活性，对多种人类癌症细胞的IC ₅₀值为0.76-3.29μM，并与硼替佐米具有协同作用。因此LP0040 代表了NAE / UAE双重抑制剂未来发展的宝贵起点。