Summary: 

The National Cancer Institute (NCI) is actively seeking potential licensees and/or co-development research collaboration partners interested in advancing oxynitidine derivatives as novel inhibitors of topoisomerase IB (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1) for cancer treatment. These TOPI and TDP1 inhibitors, when administered together, demonstrate enhanced anti-tumor efficacy.

Description of Technology: 

Topoisomerase 1B (TOP1) is an enzyme that relieves DNA torsional strain through the formation of transient TOP1-DNA covalent cleavage complexes (TOP1ccs) and is an attractive target for anti-cancer therapeutics. TOP1 inhibitors – such as camptothecin (CPT) – stabilize TOP1ccs, which ultimately leads to cell death. TOP1 inhibitors have long been recognized as anti-cancer agents and are used clinically. However, existing TOP1 inhibitor CPT, is limited by toxicity, chemical instability, poor solubility, and potential drug resistance via efflux mechanisms. Moreover, CPT directly competes with tyrosyl-DNA phosphodiesterase 1 (TDP1), which is an enzyme that repairs TOP1cc-induced cell damage. As such, this complicates CPT’s effectiveness. Overall, there is ongoing interest in finding non-CPT compounds targeting TOP1 and/or TDP1 for cancer therapy. 

Researchers at the National Cancer Institute (NCI) and their collaborators have identified a range of oxynitidine derivatives that inhibit TOP1 and/or TDP1. These compounds represent a promising alternative to CPT. These oxynitidine derivatives have demonstrated potent TOP1 inhibition at nanomolar concentrations and effectively induce DNA damage and apoptosis in cancer cell lines. Additionally, some derivatives showed synergistic effects when used in combination with CPT. In vivo studies using xenograft mouse models of colon and breast cancer cells indicated that these derivatives (1) were generally well-tolerated and safe and (2) caused dose-dependent reduction in tumor weight. Crucially, these derivatives exhibit a significantly lower likelihood of eliciting drug resistance due to reduced susceptibility to drug efflux mechanisms. Overall, this research highlights a new class of compounds with potential for enhanced therapeutic efficacy and improved tolerability compared to traditional CPT-based therapies.

The NCI is seeking research co-development opportunities and/or potential licensees to further advance these oxynitidine derivatives as novel inhibitors of TOP1 and TDP1 for cancer treatment.

Potential Commercial Applications: 

•    TOP1 and TDP1 inhibitors for treating various cancers
•    Combinatorial drug treatment options to boost anti-tumor potency

Competitive Advantages:

•    Novel chemotype for TOP1 and TDP1 inhibitors
•    Can potentially be used synergistically with existing therapeutics such as CPT
•    Limited number of chemotypes reported as TDP1 inhibitors provides good commercial potential given finite competition
•    These compounds may overcome the limitations of CPT, especially chemical instability and diarrhea