Integrated transcriptomics- and structure-based drug repositioning identifies drugs with proteasome inhibitor properties.
Humans
Proteasome Inhibitors
/ pharmacology
Drug Repositioning
/ methods
Bortezomib
/ pharmacology
Transcriptome
Proteasome Endopeptidase Complex
/ metabolism
Cell Line, Tumor
MCF-7 Cells
Molecular Docking Simulation
Antineoplastic Agents
/ pharmacology
Puromycin
/ pharmacology
Gene Expression Profiling
Cell Survival
/ drug effects
Antineoplastic agents
Drug discovery
Drug mechanism-of-action
Drug screening
Molecular docking
Transcriptomic signature
Undescribed proteasome inhibitor
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
13 08 2024
13 08 2024
Historique:
received:
23
12
2022
accepted:
05
08
2024
medline:
14
8
2024
pubmed:
14
8
2024
entrez:
13
8
2024
Statut:
epublish
Résumé
Computational pharmacogenomics can potentially identify new indications for already approved drugs and pinpoint compounds with similar mechanism-of-action. Here, we used an integrated drug repositioning approach based on transcriptomics data and structure-based virtual screening to identify compounds with gene signatures similar to three known proteasome inhibitors (PIs; bortezomib, MG-132, and MLN-2238). In vitro validation of candidate compounds was then performed to assess proteasomal proteolytic activity, accumulation of ubiquitinated proteins, cell viability, and drug-induced expression in A375 melanoma and MCF7 breast cancer cells. Using this approach, we identified six compounds with PI properties ((-)-kinetin-riboside, manumycin-A, puromycin dihydrochloride, resistomycin, tegaserod maleate, and thapsigargin). Although the docking scores pinpointed their ability to bind to the β5 subunit, our in vitro study revealed that these compounds inhibited the β1, β2, and β5 catalytic sites to some extent. As shown with bortezomib, only manumycin-A, puromycin dihydrochloride, and tegaserod maleate resulted in excessive accumulation of ubiquitinated proteins and elevated HMOX1 expression. Taken together, our integrated drug repositioning approach and subsequent in vitro validation studies identified six compounds demonstrating properties similar to proteasome inhibitors.
Identifiants
pubmed: 39138277
doi: 10.1038/s41598-024-69465-6
pii: 10.1038/s41598-024-69465-6
doi:
Substances chimiques
Proteasome Inhibitors
0
Bortezomib
69G8BD63PP
Proteasome Endopeptidase Complex
EC 3.4.25.1
Antineoplastic Agents
0
Puromycin
4A6ZS6Q2CL
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
18772Informations de copyright
© 2024. The Author(s).
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