03-15972. Government-Owned Inventions; Availability for Licensing

AGENCY:

National Institutes of Health, Public Health Service, HHS.

ACTION:

Notice.

SUMMARY:

The inventions listed below are owned by agencies of the U.S. Government and are available for licensing in the U.S. in accordance with 35 U.S.C. 207 to achieve expeditious commercialization of results of federally-funded research and development. Foreign patent applications are filed on selected inventions to extend market coverage for companies and may also be available for licensing.

ADDRESSES:

Licensing information and copies of the U.S. patent applications listed below may be obtained by writing to the indicated licensing contact at the Office of Technology Transfer, National Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-3804; telephone: [phone]; fax: [phone]. A signed Confidential Disclosure Agreement will be required to receive copies of the patent applications.

Oligodeoxyribonucleotides Comprising O⁶-Benzylguanine and Their Use

Robert Moschel et al. (NCI)

U.S. Patent 6,060,458 issued 09 May 2000,

Licensing Contact: George Pipia; 301/435-5560; [e-mail].

The DNA repair protein, O⁶-alkylguanine-DNA alkyltransferase (alkyltransferase) is the primary source of tumor cell resistance to alkylating chemotherapeutic drugs that modify the O⁶-position of DNA guanine residues. Inactivators of alkyltransferase are currently in use to enhance chemotherapy by these alkylating drugs. The prototype inactivator, O⁶-benzylguanine is currently in Phase II and III clinical trials as an adjuvant to improve chemotherapy. Although O⁶-benzylguanine is a promising inactivator, it is not an ideal drug since it is only sparingly soluble in water and it is not effective in inactivating some mutant alkyltransferase proteins that could possibly be produced after repeated chemotherapy cycles.

Oligodeoxyribonucleotides containing O⁶-benzylguanine residues represent another class of alkyltransferase inactivators. They are extremely water soluble alkyltransferase inactivators that can efficiently inactivate the alkyltransferase protein at much lower concentrations than O⁶-benzylguanine. In addition, oligodeoxyribonucleotides containing O⁶-benzylguanine are effective in activating several mutant alkyltransferase proteins that are highly resistant to inactivation by O⁶-benzylguanine. For example, oligodeoxyribonucleotides between 7 and 11 nucleotides in length containing multiple O⁶-benzylguanines are effective in inactivating several alkyltransferase molecules per oligonucleotide molecule at 300 fold lower concentrations than O⁶-benzylguanine. These same substrates are also effective inactivators of mutant alkyltransferase molecules that are resistant to inactivation by O⁶-benzylguanine. In addition, positioning O⁶-benzylguanine near the 3′-or 5′-terminus of these oligodeoxyribonucleotides improves their resistance to degradation by cellular nuclease proteins. Therefore, oligodeoxyribonucleotides containing multiple O⁶-benzylguanine residues may be more effective chemotherapy adjuvants than O⁶-benzylguanine as the free base.

Imidazoacridones with Anti-Tumor Activity

Christophe Michejda et al. (NCI) DHHS Reference No. E-289-1999 (and related U.S. and foreign patents/applications) and U.S. Patent 6,541,483 issued 01 April 2002 (and related U.S. and foreign patents/applications),

Licensing Contact: George Pipia; 301/435-5560; [e-mail].

The present invention relates to novel bifunctional molecules with anti-tumor activity. These agents are composed of an imidazoacridone moiety linked by a nitrogen containing aliphatic chain of various length and rigidity to another aromatic ring system capable of intercalation to DNA.

Previous studies on related symmetrical bis-imidazoacridones revealed that only one planar imidazoacridone moiety intercalates into DNA. The second aromatic moiety, which is crucial for biological activity, along with the linker resides in DNA minor groove, and is believed to interact with DNA-binding proteins (most likely, transcription factors and /or repair proteins). The symmetrical bis-imidazoacridones arrest the growth of sensitive cancers (especially colon cancers) but do not kill the tumors. It was hypothesized that the growth arrest was due to the inability of the affected tumor cells to repair DNA damage caused by the compounds. Remarkably, bis-imidazoacridones are very well tolerated, are very tissue selective and do not appear to damage normal tissues.

Since the binding of the symmetrical bis-imidazoacridones to DNA was unsymmetrical, the inventors have developed unsymmetrical compounds in which one imidazoacridone moieties was replaced by other intercalating groups, with the expectation that this would enhance biological activity while retaining the remarkable tissue selectivity and low systemic toxicity. The new compounds contain intercalating moieties such as 3-chloro-7-methoxyacridine or naphthalimide along with the original imidazoacridones.

These new compounds, especially those containing naphthalimide moiety, are extremely cytotoxic against variety of tumor cells in vitro (IC50 at low nanomolar range) and kill tumor cells by inducing apoptosis. In vivo, in nude mice xenografted with human tumors, the compounds significantly inhibited the growth of such tumors as colon tumor HCT116 and Colo205 as well pancreatic tumors (lines 6.03 and 10.05 freshly established from a patient). These compounds are extremely potent agents against hepatocellular carcinoma as evidenced by their ability to eradicate liver cancer in an orthotopic liver cancer model in rats. The primary molecular target of these very potent compounds is the inhibition of both topoisomerase I and II, although other targets may be important as well. Remarkably, no toxicity was observed at the therapeutic doses. These are among the most potent agents known against cancers of the GI tract and appear to be tolerated very well.

Dated: June 16, 2003.

Steven M. Ferguson,

Acting Director, Division of Technology Development and Transfer, Office of Technology Transfer, National Institutes of Health.