Inhibition of proteasome deubiquitinating activity as a new cancer therapy

Area of Science:

• Molecular Biology
• Oncology
• Drug Discovery

Background:

• The 26S proteasome degrades ubiquitin-tagged proteins, crucial for cellular regulation.
• The 20S core particle is a validated anticancer target, exemplified by bortezomib.
• The 19S regulatory particle's role in proteasomal degradation is less understood as a therapeutic target.

Purpose of the Study:

• To identify novel proteasome inhibitors targeting the 19S regulatory particle.
• To investigate the therapeutic potential of b-AP15, a novel inhibitor of 19S deubiquitinating activity.
• To explore b-AP15's efficacy in various cancer models.

Main Methods:

• Characterization of b-AP15 as a proteasome inhibitor.
• Assay of b-AP15's effect on deubiquitinating enzymes UCHL5 and USP14.
• Assessment of b-AP15-induced apoptosis in cancer cells.
• Evaluation of b-AP15's efficacy in preclinical in vivo solid tumor and leukemia models.

Main Results:

• b-AP15 inhibits the deubiquitinating activity of UCHL5 and USP14 within the 19S regulatory particle.
• b-AP15 treatment leads to polyubiquitin accumulation and tumor cell apoptosis, independent of TP53 status or BCL2.
• b-AP15 demonstrates significant inhibition of tumor progression in multiple solid tumor models.
• b-AP15 reduces organ infiltration in an acute myeloid leukemia model.

Conclusions:

• The deubiquitinating activity of the 19S regulatory particle represents a novel therapeutic target for cancer treatment.
• b-AP15 is a promising small molecule inhibitor targeting the 19S regulatory particle with broad anticancer potential.
• Targeting 19S deubiquitinases offers a new strategy for overcoming resistance mechanisms in cancer therapy.