%0 Journal Article
%T Discovery of a novel DNA polymerase inhibitor and characterization of its antiproliferative properties
%A Bhanvi Mishra
%A Ernest Y.C. Lee
%A Hong Zhao
%A Marietta Y.W.T. Lee
%A Sufang Zhang
%A Zbigniew Darzynkiewicz
%A Zhongtao Zhang
%J Archive of "Cancer Biology & Therapy".
%D 2019
%R 10.1080/15384047.2018.1529126
%X 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 ¦Ä. The discovered inhibitor, Zelpolib, is projected to bind to the active site of Pol ¦Ä when it is actively engaged in DNA replication through interactions with DNA template and primer. Zelpolib shows robust inhibition of Pol ¦Ä 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 ¦Ä is not only involved in DNA replication, it is also a key component in many DNA repair pathways. Pol ¦Ä 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
%K DNA polymerase delta
%K polymerase inhibitor
%K PARP inhibitor
%K DNA replication
%K DNA repair
%K olaparib
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422523/