Description of Invention: The invention describes compositions of tetracycline compounds and their derivatives as having anticancer activity, as well as methods of treating cancer. Tetracyclines are commonly used as antibiotics; however, testing of these compounds in a high throughput screening system revealed certain derivatives to be potent inhibitors of tyrosyl-DNA-phosphodiesterase (Tdp1).
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. This can reduce the effectiveness of camptothecins as anti-cancer agents. In addition, Tdp1 repairs free-radical-mediated DNA breaks.
As disclosed in the instant technology, tetracyclines have the potential to enhance the anti-neoplastic activity of Top1 inhibitors by reducing repair of Top1-DNA lesions through inhibition of Tdp1. Inhibition of Tdp1 may also reduce repair of DNA breaks and increase the rate of apoptosis in cancer cells, making them potential anti-cancer agents on their own.
Z Liao et al. Inhibition of human tyrosyl-DNA phosphodiesterase (Tdp1) by aminoglycoside antibiotics and ribosome inhibitors. Mol Pharmacol. 2006 Jul;70(1):366-372. [ PubMed: 16618796 ]
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 ]
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 at the National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize tetracycline derivatives, particularly optimizing them for therapeutic use. Please contact John D. Hewes, Ph.D. at 301-435-3121 or email@example.com for more information.
Portfolios: Cancer 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 Email: firstname.lastname@example.org Phone: 301-594-6565 Fax: 301-402-0220