The oligonucleotide-based fluorescence assay for the discovery of tyrosyl-DNA phosphodiesterase 2 inhibitors

Tyrosyl-DNA phosphodiesterase 2 (TDP2) plays an important role in the repair of DNA damage induced by Topoisomerase II (TOP2), and is a potential anticancer target. In this work, we established an efficient and precise fluorescence assay for TDP2 inhibitor discovery based on FRET technique. The sequent screening of our natural product library led to the identification of a new TDP2 inhibitor 3 (8.6 ± 0.35 μM), which showed synergistic effect with etoposide in HCT116 and DU145 cell lines. The possible binding mode of 3 with TDP2 protein was also studied.