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

Area of Science:

• Pharmacogenomics
• Drug Discovery
• Computational Biology

Background:

• Proteasome inhibitors (PIs) are crucial in cancer therapy.
• Identifying novel PIs or drugs with similar mechanisms is vital for expanding treatment options.

Purpose of the Study:

• To identify novel compounds with proteasome inhibitory properties using an integrated computational and in vitro approach.
• To validate candidate compounds for their ability to inhibit proteasomal activity and induce cancer cell responses.

Main Methods:

• Integrated drug repositioning using transcriptomics data and structure-based virtual screening.
• In vitro validation including proteasomal activity assays, ubiquitinated protein assessment, cell viability, and gene expression analysis.
• Screening against known proteasome inhibitors (bortezomib, MG-132, MLN-2238) in melanoma and breast cancer cell lines.

Main Results:

• Six compounds, including manumycin-A and puromycin dihydrochloride, exhibited proteasome inhibitor properties.
• Candidate compounds showed varying degrees of inhibition across catalytic sites (β1, β2, β5).
• Manumycin-A, puromycin dihydrochloride, and tegaserod maleate induced significant accumulation of ubiquitinated proteins and elevated HMOX1 expression, similar to bortezomib.

Conclusions:

• The integrated computational and in vitro approach successfully identified novel compounds with proteasome inhibitory potential.
• Manumycin-A, puromycin dihydrochloride, and tegaserod maleate demonstrate promising characteristics for drug repositioning as proteasome inhibitors.
• These findings expand the landscape of potential therapeutic agents targeting the proteasome pathway.