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.
Copyright © 2017 Elsevier Masson SAS. All rights reserved.
MeSH terms
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Adenocarcinoma / drug therapy*
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Apoptosis / drug effects
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Caco-2 Cells
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Cell Line
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Colorectal Neoplasms / drug therapy*
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / pathology
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Dose-Response Relationship, Drug
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Drug Discovery
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Humans
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Mitoxantrone / chemical synthesis
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Mitoxantrone / chemistry
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Mitoxantrone / pharmacology*
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Models, Molecular
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Molecular Structure
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NEDD8 Protein / antagonists & inhibitors*
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NEDD8 Protein / metabolism
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Structure-Activity Relationship
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Tumor Suppressor Protein p53 / antagonists & inhibitors
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Tumor Suppressor Protein p53 / metabolism
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Ubiquitin-Activating Enzymes / antagonists & inhibitors*
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Ubiquitin-Activating Enzymes / metabolism
Substances
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Enzyme Inhibitors
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NEDD8 Protein
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NEDD8 protein, human
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Tumor Suppressor Protein p53
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Mitoxantrone
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Ubiquitin-Activating Enzymes