The Anticancer Activity of a First-in-class Small-molecule Targeting PCNA

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Proliferating cell nuclear antigen (PCNA) is crucial for DNA replication, repair, and cancer cell survival.
• A cancer-associated PCNA isoform (caPCNA) with an altered L126-Y133 region is highly expressed in tumors but not normal cells.
• A peptide targeting the L126-Y133 region demonstrated selective cancer cell killing.

Purpose of the Study:

• To identify small molecules targeting the caPCNA L126-Y133 region as potential broad-spectrum anticancer agents.
• To characterize the therapeutic properties and potential toxicity of identified inhibitors.

Main Methods:

• Computer modeling and medicinal chemistry were employed to target a PCNA surface pocket.
• A potent inhibitor, AOH1160, was identified and its properties were characterized.
• In vitro and in vivo studies assessed AOH1160's efficacy and toxicity.

Main Results:

• AOH1160 selectively kills diverse cancer cells at sub-micromolar concentrations with minimal toxicity to nonmalignant cells.
• AOH1160 inhibits DNA replication, blocks DNA repair, induces cell-cycle arrest, and promotes apoptosis in cancer cells.
• AOH1160 is orally bioavailable, suppresses tumor growth in animals, and exhibits a favorable safety profile.

Conclusions:

• AOH1160 demonstrates significant potential as a broad-spectrum anticancer therapeutic.
• Targeting the caPCNA L126-Y133 region offers a promising strategy for cancer treatment.
• AOH1160 exhibits favorable therapeutic properties and a low toxicity profile, supporting its clinical development.