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  • Larsson, PeterGothenburg University,Göteborgs universitet,Sahlgrenska Centrum för Cancerforskning (SCCR),Institutionen för kliniska vetenskaper, Avdelningen för onkologi,Sahlgrenska Center for Cancer Research (SCCR),Institute of Clinical Sciences, Department of Oncology (author)

Integrated transcriptomics- and structure-based drug repositioning identifies drugs with proteasome inhibitor properties

  • Article/chapterEnglish2024

Publisher, publication year, extent ...

  • 2024

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  • LIBRIS-ID:oai:gup.ub.gu.se/340354
  • https://gup.ub.gu.se/publication/340354URI
  • https://doi.org/10.1038/s41598-024-69465-6DOI

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  • Language:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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.

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  • Rosa, MC (author)
  • Righino, Benedetta (author)
  • Olsson, MaximGothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för onkologi,Institute of Clinical Sciences, Department of Oncology(Swepub:gu)xolmax (author)
  • Florea, Bogdan Iulius (author)
  • Forssell-Aronsson, Eva,1961Gothenburg University,Göteborgs universitet,Sahlgrenska Centrum för Cancerforskning (SCCR),Institutionen för kliniska vetenskaper, Avdelningen för medicinsk strålningsvetenskap,Sahlgrenska Center for Cancer Research (SCCR),Institute of Clinical Sciences, Department of Medical Radiation Sciences(Swepub:gu)xforev (author)
  • Kovács, Anikó,1961Gothenburg University,Göteborgs universitet,Institutionen för biomedicin,Institute of Biomedicine(Swepub:gu)xkovan (author)
  • Karlsson, Per,1963Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för onkologi,Institute of Clinical Sciences, Department of Oncology(Swepub:gu)xkperd (author)
  • Helou, Khalil,1966Gothenburg University,Göteborgs universitet,Sahlgrenska Centrum för Cancerforskning (SCCR),Institutionen för kliniska vetenskaper, Avdelningen för onkologi,Sahlgrenska Center for Cancer Research (SCCR),Institute of Clinical Sciences, Department of Oncology(Swepub:gu)xhelkh (author)
  • Parris, Toshima Z,1978Gothenburg University,Göteborgs universitet,Sahlgrenska Centrum för Cancerforskning (SCCR),Institutionen för kliniska vetenskaper, Avdelningen för onkologi,Sahlgrenska Center for Cancer Research (SCCR),Institute of Clinical Sciences, Department of Oncology(Swepub:gu)xparto (author)
  • Göteborgs universitetSahlgrenska Centrum för Cancerforskning (SCCR) (creator_code:org_t)

Related titles

  • In:Scientific Reports14:12045-2322

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