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ID: ALA4270526
Journal: Eur J Med Chem
Title: A novel NAE/UAE dual inhibitor LP0040 blocks neddylation and ubiquitination leading to growth inhibition and apoptosis of cancer cells.
Authors: Lu P, Guo Y, Zhu L, Xia Y, Zhong Y, Wang Y.
Abstract: 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.
CiteXplore: 29843100