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Published on: December 1, 2016
The Anticancer Activity of a First-in-class Small-molecule Targeting PCNA
Long Gu1, Robert Lingeman2, Fumiko Yakushijin3
1Department of Molecular & Cellular Biology, Beckman Research Institute of City of Hope, Duarte, California. Lgu@coh.org.
Purpose:
Proliferating cell nuclear antigen (PCNA) plays an essential role in regulating DNA synthesis and repair and is indispensable to cancer cell growth and survival. We previously reported a novel cancer associated PCNA isoform (dubbed caPCNA), which was ubiquitously expressed in a broad range of cancer cells and tumor tissues, but not significantly in nonmalignant cells. We found the L126-Y133 region of caPCNA is structurally altered and more accessible to protein-protein interaction. A cell-permeable peptide harboring the L126-Y133 sequence blocked PCNA interaction in cancer cells and selectively kills cancer cells and xenograft tumors. On the basis of these findings, we sought small molecules targeting this peptide region as potential broad-spectrum anticancer agents.
Experimental Design:
By computer modeling and medicinal chemistry targeting a surface pocket partly delineated by the L126-Y133 region of PCNA, we identified a potent PCNA inhibitor (AOH1160) and characterized its therapeutic properties and potential toxicity.
Results:
AOH1160 selectively kills many types of cancer cells at below micromolar concentrations without causing significant toxicity to a broad range of nonmalignant cells. Mechanistically, AOH1160 interferes with DNA replication, blocks homologous recombination-mediated DNA repair, and causes cell-cycle arrest. It induces apoptosis in cancer cells and sensitizes them to cisplatin treatment. AOH1160 is orally available to animals and suppresses tumor growth in a dosage form compatible to clinical applications. Importantly, it does not cause significant toxicity at 2.5 times of an effective dose.
Conclusions:
These results demonstrated the favorable therapeutic properties and the potential of AOH1160 as a broad-spectrum therapeutic agent for cancer treatment.
Insights
A novel small molecule, AOH1160, targets a cancer-specific PCNA protein region, selectively killing cancer cells while sparing normal cells. This promising broad-spectrum anticancer agent shows therapeutic potential with low toxicity.
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.
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