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Discovery of New Catalytic Topoisomerase II Inhibitors for Anticancer Therapeutics
Victor M Matias-Barrios1, Mariia Radaeva1, Yi Song1,2
1The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Abstract:
Poison inhibitors of DNA topoisomerase II (TOP2) are clinically used drugs that cause cancer cell death by inducing DNA damage, which mechanism of action is also associated with serious side effects such as secondary malignancy and cardiotoxicity. In contrast, TOP2 catalytic inhibitors induce limited DNA damage, have low cytotoxicity, and are effective in suppressing cancer cell proliferation. They have been sought after to be prospective anticancer therapies. Herein the discovery of new TOP2 catalytic inhibitors is described. A new druggable pocket of TOP2 protein at its DNA binding domain was used as a docking site to virtually screen ~6 million molecules from the ZINC15 library. The lead compound, T60, was characterized to be a catalytic TOP2 inhibitor that binds TOP2 protein and disrupts TOP2 from interacting with DNA, resulting in no DNA cleavage. It has low cytotoxicity, but strongly inhibits cancer cell proliferation and xenograft growth. T60 also inhibits androgen receptor activity and prostate cancer cell growth. These results indicate that T60 is a promising candidate compound that can be further developed into new anticancer drugs.
Insights
New catalytic inhibitors of DNA topoisomerase II (TOP2) offer a safer approach to cancer therapy. Compound T60 effectively inhibits cancer cell proliferation and tumor growth with low cytotoxicity.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Poison inhibitors of DNA topoisomerase II (TOP2) are effective anticancer agents but cause severe side effects like cardiotoxicity and secondary malignancies.
- TOP2 catalytic inhibitors offer a promising alternative due to limited DNA damage and lower cytotoxicity, with potential for cancer therapy.
Purpose of the Study:
- To discover and characterize novel catalytic inhibitors of DNA topoisomerase II (TOP2).
- To identify compounds with potent anticancer activity and a favorable safety profile.
Main Methods:
- Virtual screening of approximately 6 million molecules from the ZINC15 library against a newly identified druggable pocket in the TOP2 DNA binding domain.
- Characterization of the lead compound T60 for its inhibitory activity, mechanism of action, cytotoxicity, and efficacy in preclinical cancer models.
Main Results:
- The lead compound T60 was identified as a catalytic TOP2 inhibitor.
- T60 disrupts TOP2-DNA interaction without inducing DNA cleavage, exhibiting low cytotoxicity.
- T60 demonstrated strong inhibition of cancer cell proliferation, xenograft tumor growth, and androgen receptor activity in prostate cancer cells.
Conclusions:
- T60 represents a promising novel catalytic TOP2 inhibitor with significant potential for development into new anticancer therapeutics.
- The discovery highlights a new druggable pocket in TOP2, opening avenues for future drug design against cancer.
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