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

Eur J Med Chem. 2018 Jun 25:154:294-304. doi: 10.1016/j.ejmech.2018.05.027.

Peng Lu ¹, Yahui Guo ², Lijuan Zhu ¹, Yineng Xia ¹, Yuejiao Zhong ³, Yubin Wang ⁴

Affiliations

1 School of Pharmaceutical Sciences, Nanjing Tech University, No. 5 Xinmofan Road, Nanjing 210009, People's Republic of China.
2 Department of Pharmaceutical Science, China Pharmaceutical University, No. 24 Tongjia Xiang, Nanjing 210009, People's Republic of China.
3 The Affiliated Cancer Hospital of Nanjing Medical University, No. 42 Baiziting, Nanjing 210009, People's Republic of China.
4 School of Pharmaceutical Sciences, Nanjing Tech University, No. 5 Xinmofan Road, Nanjing 210009, People's Republic of China. Electronic address: wyb5393@njtech.edu.cn.

PMID: 29843100 DOI: 10.1016/j.ejmech.2018.05.027

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.

Keywords

Apoptosis; Drug discovery; Dual inhibitor; NEDD8 activating enzyme; Ubiquitin activating enzyme.

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