Tyrosyl-DNA phosphodiesterase 2 (TDP2) is an enzyme that playings a critical role in repairing nucleic acid lesions, namely by repairing trapped DNA cleavage complexes. TDP2 repairs topoisomerase (TOP2)-mediated DNA damage induced by chemotherapeutic agents and removes endogenous TOP2-DNA cleavage complexes. Further, TDP2 deficiency potentiates the antiproliferative activity of TOP2 inhibitors. This suggest that combination therapies consisting of TDP2 and TOP2 inhibitors have a synergistic effect on tumor tissues. Therefore, TDP2 represents a promising anti-cancer pharmacological target as a monotherapy or as part of a combination therapy.

The NCI investigators and their collaborators have discovered a series of furoquinolinedione derivatives as specific TDP2 inhibitors that could act as anti-cancer therapeutics alone and/or potentiate the pharmacological action of TOP2 inhibitors. Systematic structure-activity relationship studies were conducted and demonstrated that several furoquinolinedione derivatives had TDP2 inhibitory activity in the low micromolar or submicromolar range. Further, enzyme-based assays showed the furoquinolinedione derivatives are specific to TDP2 and showed no inhibitory activity against TDP1 and TOP1. 

We are seeking licensing and/or co-development partners to further develop this family of compounds as anti-cancer agents.

Competitive Advantages:

• Selective inhibition of TDP2
• Can be used alone or in combination with TOP2 inhibitors
• Synergistic effect to boost the efficacy of TOP2 inhibitors (decrease effective dosage)

Commercial Applications:

• Standalone cancer therapeutic
• Part of a combination cancer therapeutic with other drugs, such as TOP2 inhibitors