Summary: 
The National Cancer Institute (NCI) is actively seeking potential licensees and/or co-development research collaboration partners interested in further developing this family of oxynitidine derivatives as tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors and radiosensitizers for the treatment of cancer. 

Description of Technology: 
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an enzyme that promotes the repair of DNA damage caused by common anti-cancer interventions, such as ionizing radiation (IR) and topoisomerase 1 (TOP1) chemotherapy. This enzyme plays a critical role in repairing the trapped DNA cleavage complexes induced by clinically used TOP1 chemotherapy (such as irinotecan and topotecan). TDP1 also plays a regulatory role in non-homologous end joining (NHEJ) in the repair of DNA double-strand breaks and damage caused by ionizing radiation. In both cases, this leads to a diminished therapeutic effect of the intervention and is a limitation of radiotherapy and the use of TOP1 chemotherapies. TDP1 deficiency can help overcome this limitation by preventing the TDP1 DNA repair activity. As such, TDP1 is a promising target for novel anti-cancer and radiosensitizing agents. Although there are reported TDP1 inhibitors to enhance chemotherapy agents, such as TOP1 inhibitors, there are no reported TDP1 inhibitors as radiosensitizers. Additionally, there are no FDA-approved TDP1 inhibitors for cancer treatment or as a radiosensitizing agent. 

Researchers at the National Cancer Institute (NCI) and their collaborators have identified a family of oxynitidine derivatives that inhibit TDP1 while enhancing the effects of ionizing radiation. In vitro, these compounds have been demonstrated to be potent TDP1 inhibitors that target, stabilize, and increase the formation of DNA cleavage complexes in various cancers – including colorectal cancer (CRC). Additionally, these compounds exhibited a strong radiosensitizing effect in vitro and in vivo in a dose-dependent-manner in CRC. The compounds, in combination with IR, reduced intracellular NHEJ, inhibited tumor growth and reduced tumor weight. These results underscore the potential use of this family of oxynitidine derivatives as therapeutic radiosensitizers and TDP1 inhibitors.  

The NCI is seeking co-development research opportunities and/or potential licensees to further advance these oxynitidine derivatives as novel inhibitors of TDP1 and radiosensitizers for the treatment of cancer.

Potential Commercial Applications: 

•    TDP1 inhibitors for treating various cancers
•    Radiosensitizing agent 
•    Combination drug treatment to boost anti-tumor potency

Competitive Advantages:

•    Can be used synergistically with TOP1 inhibitors to increase effectiveness
•    Few reported clinical trials
•    No FDA approved TDP1 inhibitors 
•    Potential for first-in-class therapeutic/radiosensitizer 
•    Can be used synergistically with ionizing radiation to increase effectiveness