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

作者：Lu, Peng; Guo, Yahui; Zhu, Lijuan; Xia, Yineng; Zhong, Yuejiao; Wang, Yubin^*

来源：European Journal of Medicinal Chemistry, 2018, 154: 294-304.

DOI：10.1016/j.ejmech.2018.05.027

• NEDD8 activating enzyme
• Ubiquitin activating enzyme
• Dual inhibitor
• Apoptosis
• Drug discovery

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 micro mole concentrations. LP0040 possessed anti-proliferation activities with IC50 values of 0.76-3.29 mu M 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.

• 出版日期2018-6-25
• 单位南京医科大学; 中国药科大学