Optimization of New Catalytic Topoisomerase II Inhibitors as an Anti-Cancer Therapy.

Abstract

Simple SummaryDNA topoisomerase II (TOP2) is a drug target for many types of cancers. However, clinically used TOP2 inhibitors not only kill cancer cells, but also damage normal cells, and can even give rise to other types of cancers. To discover new TOP2 inhibitors to more effectively treat cancer patients, we have applied computer-aided drug design technology to develop several TOP2 inhibitors that can strongly inhibit cancer cell growth but exert low side effects. Results of one exemplary compound are presented in this study. It shows several promising drug-like properties that can be potentially developed into anticancer drugs.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.