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

Ke Jia Wu, Hai Jing Zhong, Guodong Li, Chenfu LIU, Hui Min David Wang, Edmond Dik Lung MA, Chung Hang Leung*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

49 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1021-1027
Number of pages7
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 1 Jan 2018

Scopus Subject Areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

User-Defined Keywords

  • Drug repurposing
  • Mitoxantrone
  • NEDD8
  • Ubiquitin


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