Discovery of an Inhibitor of the Proteasome Subunit Rpn11

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• The proteasome is vital for protein degradation, regulating cellular processes and removing damaged proteins.
• Proteasome inhibitors are established therapeutics for multiple myeloma.
• Rpn11 is a Zn²⁺-dependent metalloisopeptidase crucial for protein ubiquitination and proteasomal degradation.

Purpose of the Study:

• To identify novel inhibitors of Rpn11 using a fragment-based drug discovery approach.
• To develop potent and selective small molecules targeting Rpn11 for potential anti-cancer applications.

Main Methods:

• Screening of a metal-binding pharmacophore library against Rpn11.
• Utilizing a fragment-based drug discovery (FBDD) strategy.
• Chemical synthesis and optimization of identified hit compounds.

Main Results:

• 8-thioquinoline (8TQ) showed significant Rpn11 inhibition (IC₅₀ ∼2.5 μM).
• Synthetic elaboration of 8TQ led to compound 35 with enhanced potency (IC₅₀ ∼400 nM).
• Compound 35 demonstrated potent and selective Rpn11 inhibition and blocked tumor cell proliferation in vitro.

Conclusions:

• Fragment-based screening successfully identified Rpn11 inhibitors.
• Optimized small molecule 35 is a potent Rpn11 inhibitor with anti-proliferative activity.
• This study provides a promising lead compound for developing novel proteasome-targeted cancer therapies.