A novel NAE/UAE dual inhibitor LP0040 blocks neddylation and ubiquitination leading to growth inhibition and apoptosis of cancer cells.

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.