The rational discovery of multipurpose inhibitors of the ornithine decarboxylase.
A549 Cells
Animals
Antineoplastic Agents
/ chemistry
Biocatalysis
/ drug effects
Cell Survival
/ drug effects
Female
High-Throughput Screening Assays
/ methods
Humans
Mice, Inbred BALB C
Mice, Nude
Neoplasms
/ drug therapy
Ornithine
/ metabolism
Ornithine Decarboxylase
/ chemistry
Ornithine Decarboxylase Inhibitors
/ chemistry
Protein Binding
/ drug effects
Putrescine
/ metabolism
Xenograft Model Antitumor Assays
/ methods
inhibitor
negative screening
ornithine decarboxylase
protein-protein interaction
stabilizer
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
19
05
2020
revised:
30
06
2020
accepted:
20
07
2020
pubmed:
9
8
2020
medline:
23
3
2021
entrez:
9
8
2020
Statut:
ppublish
Résumé
Metabolic reprograming is a hallmark of cancer, and the polyamine metabolic network is dysregulated in many cancers. Ornithine decarboxylase (ODC) is a rate-limiting enzyme for polyamine synthesis in the polyamine metabolic network. In many cancer cells, ODC is over-expressed, so this enzyme has been an attracting anti-cancer drug target. In the catalysis axis (pathway), ODC converts ornithine to putrescine. Meanwhile, ODC's activity is regulated by protein-protein interactions (PPIs), including the ODC-OAZ1-AZIN1 PPI axis and its monomer-dimer equilibrium. Previous studies showed that when ODC's activity is inhibited, the PPIs might counteract the inhibition efficiency. Therefore, we proposed that multipurpose inhibitors that can simultaneously inhibit ODC's activity and perturb the PPIs would be very valuable as drug candidates and molecular tools. To discover multipurpose ODC inhibitors, we established a computational pipeline by combining positive screening and negative screening. We used this pipeline for the forward screening of multipurpose ligands that might inhibit ODC's activity, block ODC-OAZ1 interaction and enhance ODC non-functional dimerization. With a combination of different experimental assays, we identified three multipurpose ODC inhibitors. At last, we showed that one of these inhibitors is a promising drug candidate. This work demonstrated that our computational pipeline is useful for discovering multipurpose ODC inhibitors, and multipurpose inhibitors would be very valuable. Similar with ODC, there are a lot of proteins in human proteome that act as both enzymes and PPI components. Therefore, this work is not only presenting new molecular tools for polyamine study, but also providing potential insights and protocols for discovering multipurpose inhibitors to target more important protein targets.
Identifiants
pubmed: 32767470
doi: 10.1096/fj.202001222R
doi:
Substances chimiques
Antineoplastic Agents
0
Ornithine Decarboxylase Inhibitors
0
Ornithine
E524N2IXA3
Ornithine Decarboxylase
EC 4.1.1.17
Putrescine
V10TVZ52E4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
10907-12921Informations de copyright
© 2020 Federation of American Societies for Experimental Biology.
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