Tyrosyl-DNA phosphodiesterase (Tdp1) is an enzyme that repairs topoisomerase I (Top1)-mediated DNA damage induced by chemotherapeutic agents (such as camptothecins) and ubiquitous DNA lesions that interfere with transcription and replication.  Tdp1 is a relevant target for anticancer therapies due to its role in repairing Top1-mediated DNA damage and DNA damage associated with DNA strand breaks.  Tdp1 inhibitors are expected to be effective in cancer treatment when used in combination with Top1 inhibitors.

The current invention is Me-3,4 dephostatin, and more generally protein-tyrosine phosphatase inhibitors, which is a Tdp1 inhibitor.  Me-3,4 dephostatin could potentiate the pharmacological action of Top1 inhibitors.

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.

Publication:
S Antony et al.  Novel high-throughput electrochemiluminescent assay for identification of human tyrosyl-DNA phosphodiesterase (Tdp1) inhibitors and characterization for furamidine (NSC 305831) as an inhibitor of Tdp1.  Nucleic Acid Res. 2007;35(13):4474-4484.  [PubMed abs]

U.S. Provisional Application No. 61/042,706 filed 04 Apr 2008 (HHS Reference No. E-121-2008/0-US-01)

Inventors: 
Yves Pommier (NCI) et al.

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