Functional Proteomics of Quinazolin-4-One Derivatives Targeting the Proteasome

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Proteomics

Background:

• Quinazolinones are versatile scaffolds with diverse biological activities.
• They are recognized for their potential in developing novel therapeutic agents.
• Previous research highlights their antifungal, antitubercular, antihypertensive, anticancer, and antiviral properties.

Purpose of the Study:

• To synthesize and evaluate new 4-(3-H)-quinazolinone derivatives for anticancer activity.
• To identify the specific biological targets of the most potent compound.
• To explore the potential of these compounds as novel anticancer drugs.

Main Methods:

• Synthesis of a focused library of 4-(3-H)-quinazolinones.
• Cytotoxicity assays against DU-145 prostate cancer cells.
• Interactome profiling using drug affinity responsive target stability (DARTS) and targeted limited proteolysis-multiple reaction monitoring-mass spectrometry (t-LiP-MRM-MS).
• In vitro and in silico studies to analyze protein-ligand interactions.
• Functional analysis in living DU-145 cells.

Main Results:

• Compound 4k demonstrated significant cytotoxic activity against DU-145 prostate cancer cells.
• Proteasome subunits, particularly the β-5 subunit, were identified as key biological targets of compound 4k.
• Compound 4k was confirmed as an inhibitor of the chymotrypsin-like activity of the proteasomal β-5 subunit.
• In vitro and in silico analyses provided insights into protein-ligand interactions.

Conclusions:

• Compound 4k is a potent novel quinazolinone-based inhibitor of the proteasomal β-5 subunit.
• The identified mechanism of action suggests potential for developing new anticancer therapeutics.
• This study provides a framework for further development of quinazolinone derivatives as anticancer agents.