Tyrosyl-DNA phosphodiesterase (Tdp1) is an enzyme that repairs topoisomerase I (Top1)-mediated DNA damage induced by chemotherapeutic agents and ubiquitous DNA lesions that interfere with transcription.  The current technology are steroid derivatives that inhibit human Tdp1.

Currently, there are various types of Top1 inhibitors used in chemotherapy, e.g., camptothecin.  However, Tdp1 inhibitors are expected to be effective in combination therapy with Top1 inhibitors for the treatment of cancers.  Combining Tdp1 inhibitors with Top1 inhibitors would allow Tdp1 to potentiate the antiproliferative activity of Top1 inhibitors.  In addition to Tdp1’s effect on Top1, Tdp1 inhibitors can also exhibit antitumor activity independently, as tumors are shown to have excess free radicals, and Tdp1 repairs DNA damage by oxygen radicals.

Applications and Modality: 
It is anticipated that Tdp1 inhibitors in association with Top1 inhibitors can have selective activity toward tumor tissues.  Tdp1 inhibitors may exhibit antitumor activity by themselves because tumors have excess free radicals.

Patent Status:

U.S. Provisional Application No. 61/000,430 filed 24 Oct 2007 (HHS Reference No. E-130-2007/1-US-01)

PCT Application No. PCT/US2008/004541 filed 05 Apr 2008, claiming priority to 05 Apr 2007 (HHS Reference No. E-130-2007/2-PCT-01)

Inventors: 
Yves Pommier et al. (NCI)

Licensees Sought: 
Available for exclusive and non-exclusive licensing.

Collaborative Research Opportunity: 
The National Cancer Institute, Center for Cancer Research, Laboratory of Molecular Pharmacology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize inhibitors of Tyrosyl-DNA phosphodiesterase (Tdp1).  Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.