Structure-based identification of a NEDD8-activating enzyme inhibitor via drug repurposing

Eur J Med Chem. 2018 Jan 1:143:1021-1027. doi: 10.1016/j.ejmech.2017.11.101.

Ke-Jia Wu ¹, Hai-Jing Zhong ¹, Guodong Li ¹, Chenfu Liu ², Hui-Min David Wang ³, Dik-Lung Ma ⁴, Chung-Hang Leung ⁵

Affiliations

1 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
2 Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
3 Graduate Institute of Biomedical Engineering, National Chung Hsing University, Taichung, 402, Taiwan.
4 Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China. Electronic address: edmondma@hkbu.edu.hk.
5 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. Electronic address: duncanleung@umac.mo.

PMID: 29232579 DOI: 10.1016/j.ejmech.2017.11.101

Abstract

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.

Keywords

Drug repurposing; Mitoxantrone; NEDD8; Ubiquitin.

Name
Email *

	Sorry, but the email address you supplied was invalid.