Cancers, Vol. 13, Pages 3675: Optimization of New Catalytic Topoisomerase II Inhibitors as an Anti-Cancer Therapy
Cancers, Vol. 13, Pages 3675: Optimization of New Catalytic Topoisomerase II Inhibitors as an Anti-Cancer Therapy
Cancers doi: 10.3390/cancers13153675
Authors:
Victor M. Matias-Barrios
Mariia Radaeva
Chia-Hao Ho
Joseph Lee
Hans Adomat
Nada Lallous
Artem Cherkasov
Xuesen Dong
Clinically used topoisomerase II (TOP2) inhibitors are poison inhibitors that induce DNA damage to cause cancer cell death. However, they can also destroy benign cells and thereby show serious side effects, including cardiotoxicity and drug-induced secondary malignancy. New TOP2 inhibitors with a different mechanism of action (MOA), such as catalytic TOP2 inhibitors, are needed to more effectively control tumor growth. We have applied computer-aided drug design to develop a new group of small molecule inhibitors that are derivatives of our previously identified lead compound T60. Particularly, the compound T638 has shown improved solubility and microsomal stability. It is a catalytic TOP2 inhibitor that potently suppresses TOP2 activity. T638 has a novel MOA by which it binds TOP2 proteins and blocks TOP2–DNA interaction. T638 strongly inhibits cancer cell growth, but exhibits limited genotoxicity to cells. These results indicate that T638 is a promising drug candidate that warrants further development into clinically used anticancer drugs.
Source: Cancers - Category: Cancer & Oncology Authors: Victor M. Matias-Barrios Mariia Radaeva Chia-Hao Ho Joseph Lee Hans Adomat Nada Lallous Artem Cherkasov Xuesen Dong Tags: Article Source Type: research
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