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. Epub 2017 Dec 6.

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.

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Apoptosis / drug effects
  • Caco-2 Cells
  • Cell Line
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Mitoxantrone / chemical synthesis
  • Mitoxantrone / chemistry
  • Mitoxantrone / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • NEDD8 Protein / antagonists & inhibitors*
  • NEDD8 Protein / metabolism
  • Structure-Activity Relationship
  • Tumor Suppressor Protein p53 / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitin-Activating Enzymes / antagonists & inhibitors*
  • Ubiquitin-Activating Enzymes / metabolism

Substances

  • Enzyme Inhibitors
  • NEDD8 Protein
  • NEDD8 protein, human
  • Tumor Suppressor Protein p53
  • Mitoxantrone
  • Ubiquitin-Activating Enzymes