Identification and characterization of topoisomerase III beta poisons

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 120; no. 34; p. e2218483120
• Main Authors: Wang, Wenjie, Saha, Sourav, Yang, Xi, Pommier, Yves, Huang, Shar-Yin N
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 22.08.2023
• Subjects: Biological Sciences; Cell Line; Cell lines; Cytotoxicity; DNA topoisomerase III; DNA Topoisomerases, Type I - metabolism; Lead compounds; Poisons; R-loops; RNA; Topoisomerase I Inhibitors - chemistry; TOP3B; anti-cancer; inhibitor screen
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2218483120

We designed and carried out a high-throughput screen for compounds that trap topoisomerase III beta (TOP3B poisons) by developing a Comparative Cellular Cytotoxicity Screen. We found a bisacridine compound NSC690634 and a thiacyanine compound NSC96932 that preferentially sensitize cell lines expressing TOP3B, indicating that they target TOP3B. These compounds trap TOP3B cleavage complex (TOP3Bcc) in cells and in vitro and predominately act on RNA, leading to high levels of RNA-TOP3Bccs. NSC690634 also leads to enhanced R-loops in a TOP3B-dependent manner. Preliminary structural activity studies show that the lengths of linkers between the two aromatic moieties in each compound are critical; altering the linker length completely abolishes the trapping of TOP3Bccs. Both of our lead compounds share a similar structural motif, which can serve as a base for further modification. They may also serve in anticancer, antiviral, and/or basic research applications.