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: [email protected].
  • 5. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. Electronic address: [email protected].
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.