Anh T.Q. Cong, MS
Cardioprotection by Topoisomerase II Isoform-Selective Inhibitors
Abstract
Cancer is a major global health burden and the leading cause of death in the U.S. Many cancer types are treated with anthracyclines as chemotherapy. Anthracyclines trap Topoisomerase II (TOP2) in a DNA cleavage complex and cause lethal DNA double-strand break accumulation. Human TOP2 (TOP2A and TOP2B) are structurally and mechanistically similar. TOP2A is an effective oncogenic target, but off-target inhibition of TOP2B causes DNA damage in the heart, which leads to irreversible and dose-dependent cardiac damage in patients. Catalytic inhibition of TOP2 prevents anthracyclines from binding, but selectivity for TOP2B is needed to ensure cardioprotection does not interfere with anthracycline efficacy. This proposal presents the discovery of a new drug-binding site on TOP2 that allows catalytic inhibition and contains unique residues for isoform-selective targeting. A new class of TOP2 inhibitors is being developed and characterized with improved TOP2B-selectivity and cardioprotection.
I am deeply grateful and honored to receive a Predoctoral Fellowship in Drug Discovery from the PhRMA Foundation. This opportunity fuels my motivation to contribute to groundbreaking research that can transform the quality of life for cancer patients and survivors. With this support, I am eager to continue my research in drug development and deepen my commitment to making a meaningful impact in the scientific community.
