Discovery of deoxyvasicinone derivatives as inhibitors of NEDD8-activating enzyme

Hai Jing Zhong, Ka Ho Leung, Sheng Lin, Daniel Shiu Hin Chan, Simon Q B HAN, Sharon Lai Fung Chan, Edmond Dik Lung MA, Chung Hang Leung*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

NEDD8-activating enzyme (NAE) controls the specific degradation of proteins regulated by cullin-RING ubiquitin E3 ligases, and has been considered as an attractive molecular target for the development of drugs against cancer. A pharmacophore model constructed from a training set of deoxyvasicinone derivatives was used to screen 376 compounds from an analogue database. From the initial screening, the valine-linked deoxyvasicinone derivative 9 and the N-isopropyl-linked deoxyvasicinone derivative 10 emerged as the top scoring candidates. Compounds 9 and 10 showed micromolar potencies in both cell-free and cell-based systems, with selectivity for NAE over the related enzymes SAE and UAE. Molecular modelling analysis suggested that 9 and 10 may inhibit NAE by blocking the ATP-binding domain. Thus, these deoxyvasicinone derivatives could be considered as promising lead molecules for the development of more potent inhibitors of NAE.

Original languageEnglish
Pages (from-to)71-76
Number of pages6
JournalMethods
Volume71
Issue numberC
DOIs
Publication statusPublished - 2015

Scopus Subject Areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)

User-Defined Keywords

  • Deoxyvasicinone
  • Drug discovery
  • NEDD8
  • Pharmacophore
  • Ubiquitin-like

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