Topoisomerase III (TOP3) Inhibitors as Antiviral and Anticancer Compounds based on Bisacridines

Abstract:

• Topoisomerase 3B (TOP3B) is the only topoisomerase that can act on RNA as well as DNA. Thus, it is a target of interest for the development of cancer therapies and RNA viral infection therapies. TOP3B is not an essential gene for carcinogenesis, but a subset of cancer cells with pre-existing genome instability are particularly vulnerable to the inactivation of TOP3B. While inhibitors for other topoisomerases are among the most potent and widely used anticancer agents, there are no known inhibitors of TOP3B. In RNA viral infections, TOP3B has been implicated as a host factor for the replication of positive strand RNA viruses, particularly flaviviruses (i.e., Zika, West Nile, and Dengue) and coronaviruses (i.e., SARS-Cov1 and -2). TOP3B RNA-cleavage complexes (TOP3Bccs) could be targeted and trapped by inhibitors, causing persistent RNA damage to block viral RNA replication. This mechanism resembles the one employed by inhibitors of topoisomerases 1 and 2, which block DNA replication of cancer cells. TOP3B inhibitors could thus be valuable RNA virus drugs and anticancer drugs. However, to date, no TOP3B inhibitors have been approved for antiviral or anticancer applications.
• Researchers at NCI have discovered a class of TOP3B inhibitors based on bisacridines for anticancer and/or antiviral applications. The compounds have been shown to enhance and stabilize RNA TOP3Bccs, induce RNA TOP3Bccs in a dose and time dependent manner. Also, they preferentially effect on RNA TOP3Bccs compared to DNA TOP3Bccs in vitro. Further, preliminary structure-activity relationship analysis revealed that the linker between the acridine moieties is critical in modulating efficacy of this family of compounds. Bisacridines without linkers had very little effect on TOP3Bcc levels and bisacridines with longer linkers lead to a reduction to TOP3Bcc levels.  Induction and stabilization of these complexes would be the initiating events for cancer cell death and inhibiting RNA-viral replication. Overall, these compounds have been shown to be potent inhibitors of TOP3B.
• The NCI is seeking co-development research collaborations and/or licensees to further develop these bisacridine-based TOP3B inhibitors into antiviral and/or anticancer agents.

Competitive Advantages:

• First-in-class TOP3B inhibitors for both anticancer and antiviral applications
• RNA-based mechanism distinct from currently used and approved TOP1 and TOP2 inhibitors based on DNA
• Time- and dose-dependent effect on RNA TOB3Bccs 

Commercial Applications:

• COVID-19 and other RNA-viral infection therapy
• Anticancer agents 
• Molecular probes to study the biology of TOP3B