| Autor: |
Linda H. Malkas, David Horne, Karen L. Reckamp, Yanhong Shi, Timothy W. Synold, Steven L. Vonderfecht, Yuan Chen, Yate-Ching Yuan, Jeremy M. Stark, Robert J. Hickey, Hongzhi Li, Weidong Hu, Jianfei Chao, Qi Cui, Emily Sun, Fumiko Yakushijin, Robert Lingeman, Long Gu |
| Rok vydání: |
2023 |
| DOI: |
10.1158/1078-0432.c.6527253.v1 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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