Discovery of a Novel DNA Polymerase Inhibitor and Characterization of its Antiproliferative Properties
Biochemistry and Molecular Biology
Chromosomal duplication is targeted by various chemotherapeutic agents for the treatment of cancer. However, there is no specific inhibitor of DNA polymerases that is viable for cancer management. Through structure-based in silico screening of the ZINC database, we identified a specific inhibitor of DNA polymerase delta. The discovered inhibitor, Zelpolib, is projected to bind to the active site of Pol delta when it is actively engaged in DNA replication through interactions with DNA template and primer. Zelpolib shows robust inhibition of Pol delta activity in reconstituted DNA replication assays. Under cellular conditions, Zelpolib is taken up readily by cancer cells and inhibits DNA replication in assays to assess global DNA synthesis or single-molecule bases by DNA fiber fluorography. In addition, we show that Zelpolib displays superior antiproliferative properties to methotrexate, 5-flourouracil, and cisplatin in triple-negative breast cancer cell line, pancreatic cancer cell line and platinum-resistant pancreatic cancer cell line. Pol delta is not only involved in DNA replication, it is also a key component in many DNA repair pathways. Pol delta is the key enzyme responsible for D-loop extension during homologous recombination. Indeed, Zelpolib shows robust inhibition of homologous recombination repair of DNA double-strand breaks and induces "BRCAness" in HR-proficient cancer cells and enhances their sensitivity to PARP inhibitors.
Mishra, B., Zhang, S., Zhao, H., Darzynkiewicz, Z., Lee, E., Lee, M., & Zhang, Z. (2019). Discovery of a Novel DNA Polymerase Inhibitor and Characterization of its Antiproliferative Properties. Cancer Biology & Therapy, 20 (4), 474-486. https://doi.org/10.1080/15384047.2018.1529126