State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
Eur J Med Chem. 2018 Jan 1;143:1021-1027. doi: 10.1016/j.ejmech.2017.11.101. Epub 2017 Dec 6.
NEDD8-activating enzyme (NAE) is an essential player of the NEDD8 conjugation pathway that regulates protein degradation. Meanwhile, drug repurposing is a cost-efficient strategy to identify new therapeutic uses for existing scaffolds. In this report, mitoxantrone (1) was repurposed as an inhibitor of NAE by virtual screening of an FDA-approved drug database. Compound 1 inhibited NAE activity in cell-free and cell-based systems with high selectivity and was competitive with ATP. Furthermore, compound 1 induced apoptosis of colorectal adenocarcinoma cancer cells through inhibiting the degradation of the neddylation substrate p53.
NEDD8-激活酶 (NAE) 是 NEDD8 缀合途径的关键酶，可调节蛋白质降解。同时，药物再利用是一种经济高效的策略，可用于确定现有支架的新治疗用途。在本报告中，米托蒽醌 (1) 通过对 FDA 批准药物数据库的虚拟筛选被重新用作 NAE 的抑制剂。化合物 1 在无细胞和基于细胞的系统中具有高选择性和 ATP 竞争性抑制 NAE 活性。此外，化合物 1 通过抑制 neddylation 底物 p53 的降解诱导结直肠腺癌癌细胞凋亡。
