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Diamidine Inhibitors of Tdp1 as Anti-Cancer Agents

Posted Mar 03 2011 7:00pm

Description of Invention:
Available for licensing and commercial development are methods and compositions for treating cancer, using novel compounds derived from diamidine. Diamidine and its derivatives are potent inhibitors of tyrosyl-DNA-phosphodiesterase (Tdp1), which may be useful in chemotherapy.

Camptothecins are effective Topoisomerase I (Top1) inhibitors, and two derivatives (Topotecan® and Camptosar®) are currently approved for treatment of ovarian and colorectal cancer. Camptothecins damage DNA by trapping covalent complexes between the Top1 catalytic tyrosine and the 3’-end of the broken DNA. Tdp1 repairs Top1-DNA covalent complexes by hydrolyzing the tyrosyl-DNA bond. Thus, the presence and activity of Tdp1 can reduce the effectiveness of camptothecins as anti-cancer agents. In addition, Tdp1 repairs free-radical-mediated DNA breaks.

Inhibition of Tdp1 using diamidine or its derivatives, may reduce repair of DNA breaks and increase the rate of apoptosis in cancer cells. In addition, diamidine derivatives have the potential to enhance the anti-neoplastic activity of Top1 inhibitors, by reducing repair of Top1-DNA lesions through inhibition of Tdp1.

Development Status:
Pre-clinical stage

Yves G Pommier (NCI)
Christophe R Marchand (NCI)

Patent Status:
HHS, Reference No. E-165-2006/0
US, Application No. 12/225,672 filed 26 Sep 2008

Relevant Publication:
  1. Z Liao et al. Inhibition of human tyrosyl-DNA phosphodiesterase by aminoglycoside antibiotics and ribosome inhibitors. Mol Pharmacol. 2006 Jul;70(1):366-372. [ PubMed: 16618796 ]
  2. Y Pommier. Camptothecins and topoisomerase I: a foot in the door. Targeting the genome beyond topoisomerase I with camptothecins and novel anticancer drugs: importance of DNA replication, repair and cell cycle checkpoints. Curr Med Chem Anticancer Agents. 2004 Sep; 4(5):429-434. Review. [ PubMed: 15379698 ]
  3. Y Pommier et al. Repair of and checkpoint response to topoisomerase I mediated DNA damage. Mutat Res. 2003 Nov 27;532(1-2):173-203. Review. [ PubMed: 14643436 ]

Licensing Status:
Available for licensing.

Collaborative Research Opportunity:
The Laboratory of Molecular Pharmacology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Tdp1 inhibitors for the treatment of cancers. Please contact John D. Hewes, Ph.D. at 301-435-3121 or for more information.

Cancer - Therapeutics

For Licensing Information Please Contact:
Betty Tong Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Phone: 301-594-6565
Fax: 301-402-0220

Ref No: 1366

Updated: 03/2011

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