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

• Published in: Biomolecules & therapeutics Vol. 29; no. 5; pp. 562 - 570
• Main Authors: Jeon, Kyung-Hwa, Shrestha, Aarajana, Jang, Hae Jin, Kim, Jeong-Ahn, Sheen, Naeun, Seo, Minjung, Lee, Eung-Seok, Kwon, Youngjoo
• Format: Journal Article
• Language: English
• Published: Korea (South) The Korean Society of Applied Pharmacology 01.09.2021; 한국응용약물학회
• Subjects: Original; 약학; Topoisomerase IIα; DNA minor groove binder; Topoisomerase catalytic inhibitor; Trifluoromethyl 2-(3-trifluoromethylphenyl)-4-(3-h; Halogenated 2,4-diphenyl Indeno[1,2-b]-pyridinol derivative
• ISSN: 1976-9148; 2005-4483
• DOI: 10.4062/biomolther.2020.231

Topoisomerase IIα has been a representative anti-cancer target for decades thanks to its functional necessity in highly proliferative cancer cells. As type of topoisomerase IIα 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 IIα through the alternative mechanism of enzymatic regulation. As a catalytic inhibitor of topoisomerase IIα, 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 IIα inhibitory activity through binding to minor groove of DNA double helix and showed synergistic effects with tamoxifen in antiproliferative activity.