Anticancer Activity of Indeno[1,2-b]-Pyridinol Derivative as a New DNA Minor Groove Binding Catalytic Inhibitor of Topoisomerase IIα

Topoisomerase II alpha has been a representative anti-cancer target for decades thanks to its functional necessity in highly proliferative cancer cells. As type of topoisomerase Ila targeting drugs, topoisomerase II poisons are frequently in clinical usage. However, topoisomerase II poisons result in crucial consequences resulted from mechanistically induced DNA toxicity. For this reason, it is needed to develop catalytic inhibitors of topoisomerase II alpha through the alternative mechanism of enzymatic regulation. As a catalytic inhibitor of topoisomerase II alpha, AK-I-191 was previously reported for its enzyme inhibitory activity. In this study, we clarified the mechanism of AK-I-191 and conducted various types of spectroscopic and biological evaluations for deeper understanding of its mechanism of action. Conclusively, AK-I-191 represented potent topoisomerase II alpha inhibitory activity through binding to minor groove of DNA double helix and showed synergistic effects with tamoxifen in anti-proliferative activity.

Automated summary

Topoisomerase II alpha has been a significant anti-cancer target due to its functional necessity in highly proliferative cancer cells. Topoisomerase II poisons, as drugs targeting IIa, are commonly used in clinical settings but can cause DNA toxicity, necessitating the development of catalytic inhibitors through alternative mechanisms. AK-I-191, as a catalytic inhibitor, exhibits potent inhibitory activity and synergistic effects with tamoxifen in anti-proliferative activity.