We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Integrated transcriptomics- and structure-based drug repositioning identifies drugs with proteasome inhibitor properties.
- Authors
Larsson, Peter; De Rosa, Maria Cristina; Righino, Benedetta; Olsson, Maxim; Florea, Bogdan Iulius; Forssell-Aronsson, Eva; Kovács, Anikó; Karlsson, Per; Helou, Khalil; Parris, Toshima Z.
- Abstract
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.
- Subjects
DRUG repositioning; PROTEASOME inhibitors; BORTEZOMIB; DRUG side effects; DOSAGE forms of drugs; PHARMACOGENOMICS; PROTEASOMES
- Publication
Scientific Reports, 2024, Vol 14, Issue 1, p1
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/s41598-024-69465-6