Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11

Area of Science:

• Molecular Biology
• Biochemistry
• Cancer Research

Background:

• The proteasome is crucial for protein homeostasis, particularly in multiple myeloma and other cancers.
• Current proteasome inhibitors like bortezomib and carfilzomib have limitations, including patient non-response and acquired resistance.
• There is a significant need for novel proteostasis inhibitors with different mechanisms of action.

Purpose of the Study:

• To identify and characterize novel proteasome inhibitors targeting mechanisms beyond 20S peptidase activity.
• To evaluate the efficacy of a newly identified inhibitor, capzimin, in preclinical cancer models.

Main Methods:

• Identification of quinoline-8-thiol (8TQ) as a first-in-class inhibitor of the proteasome 19S subunit Rpn11.
• Characterization of capzimin, a derivative of 8TQ, for its selectivity against Rpn11 and other metalloenzymes.
• Assessment of capzimin's effects on proteasome substrates, unfolded protein response, and cancer cell proliferation.
• Proteomic analysis to identify capzimin-stabilized substrates.

Main Results:

• Capzimin demonstrated high selectivity for Rpn11 over related JAMM proteases and other metalloenzymes.
• Capzimin treatment led to the stabilization of proteasome substrates and induced an unfolded protein response.
• Capzimin effectively inhibited the proliferation of various cancer cells, including those resistant to bortezomib.
• Proteomic studies confirmed that capzimin stabilizes a specific subset of polyubiquitinated substrates.

Conclusions:

• Capzimin represents a novel class of proteasome inhibitors targeting the Rpn11 subunit.
• This discovery provides a promising alternative therapeutic strategy for multiple myeloma and other cancers.
• Capzimin's efficacy against drug-resistant cancer cells highlights its potential to overcome current treatment limitations.