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Matias Barrios, Victor Manuel

University of British Columbia

Topoisomerase II (TOP2) is a ubiquitous enzyme in human cells that regulates DNA topology and chromatid separation, which is critical for cells to grow and survive. Popular chemotherapeutics (such as doxorubicin and etoposide) are TOP2 poison inhibitors that induce DNA double-stranded breaks, thereby cytotoxicity to initiate cancer cell death. However, they have significant side effects such as secondary malignancy and cardiotoxicity. TOP2 catalytic inhibitors, on the other hand, cause minimal DNA disruption, have low cytotoxicity, and are efficient at inhibiting cancer cell proliferation. They are sought after as potential anticancer treatments. The development of modern TOP2 catalytic inhibitors is discussed in this thesis. We used a computer-aided drug discovery (CADD) campaign to screen over 6 million molecules from the ZINC15 database through a new druggable pocket of TOP2 protein at its DNA binding domain. T60, the lead drug, is demonstrated to be a catalytic TOP2 enzyme Inhibitor. We defined the mechanism of action of T60 as that it binds TOP2 proteins and blocks TOP2 protein from interacting with DNA thereby preventing TOP2-mediated DNA cleavage. It has low cytotoxicity but effectively inhibits cancer cell proliferation and xenograft growth. T60 also reduces the functions of the androgen receptor and blocks prostate cancer cell growth. Based on these results, we conclude that T60 is a promising candidate compound for the development of new anticancer medications.

Text

2021-06-03

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/78516

Reproductive and Developmental Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/