National Institutes of Health, Public Health Service, HHS.
This technology describes a novel class of Topoisomerase II (top2) inhibitors that are useful in treating cancer. Drugs that inhibit the top2 enzyme are among the most active anticancer agents discovered. However, many of the currently available inhibitors produce toxic side effects, have poor pharmacokinetics, or eventually become ineffective because malignant cells readily acquire resistance. Therefore, there is a need for developing new top2 inhibitor drugs that will overcome these limitations.
Azatoxin and its derivatives, which are derived by combining two parent compounds etoposide and ellipticine, are the first compounds rationally designed as inhibitors of top2. Azatoxins are also potent inhibitors of tubulin polymerization. These two anti-cancer activities can be successfully separated by synthesizing azatoxin derivatives to yield compounds which can be pharmacologically advantageous against tumor proliferation. The azatoxin platform represents an unexploited class of top2 inhibitors that could be developed into especially potent chemotherapeutics.
Competitive Advantage of Our Technology
Currently, several top2 inhibitors are approved for clinical use; however, they produce serious side effects. Etoposide, for example, causes problems with myelosuppression, drug resistance, and has poor bioavailability. Moreover, it appears to have carcinogenic properties as it has been linked to the development of acute myelogenous leukemia—an effect also observed with mitoxantrone. Anthracyclines, like doxorubicin, have the same limitations as etoposide, but they also possess cardiotoxic effects. Azatoxins have the potential to be developed into chemotherapeutics that outperform these currently used top2 inhibitors.
Azatoxins have been substantially characterized through years of pre-clinical research demonstrating that Start Printed Page 18586they possess properties from both of its parental compounds, etoposide and ellipticine. They act by stabilizing the top2-DNA cleavage complex, like etoposide does, instead of inhibiting top2 catalytic activity, the mechanism by which ellipticine acts. With regard to DNA cleavage activity, azatoxins show similar activity to etoposide. In addition to acting as a top2 inhibitor, azatoxin is also a potent inhibitor of tubulin polymerization.
The anti-cancer activity of azatoxins has been validated by cell line screening. The Developmental Therapeutics Program (DTP) of the National Cancer Institute (NCI) has tested azatoxins in its tumor cell panel and established their effectiveness against disseminated leukemia and localized tumors, such as non-small cell lung and colon cancer. These results are very encouraging showing that certain azatoxin derivatives are 100 times more active than etoposide, which is the common top2 inhibitor used in chemotherapy. Azatoxins are a novel class of potent top2 and/or tubulin inhibitors that could outperform current chemotherapeutic agents.
Topoisomerase enzymes are critical for normal cell division because they prevent tangles and knots from forming during DNA replication by cleaving and religating DNA. Several compounds have been discovered that block topoisomerases and stop its ability to religate DNA resulting in an increased number of double strand DNA breaks that kill the cell. These inhibitors are especially effective against rapidly dividing malignant cells that express high levels of top2, which represents a main reason these top2 enzymes have become an important therapeutic target. The problem is that currently used drugs are limited by their toxicity, insolubility, and their susceptibility to induce drug resistance.
In an effort to produce top2 inhibitors with increased therapeutic efficiency, well established top2 inhibitors were compared by molecular modeling to produce a composite top2 inhibitor pharmacophore of the diverse inhibitors. Based on this model, azatoxin was designed as an analogue hybrid of etoposide and ellipticine. Subsequently, several modifications of azatoxin have been synthesized to generate derivatives, such as anilinoazatoxins, which have improved pharmacological profiles.
Despite further discoveries leading to a greater understanding and treating of cancer, it continues to be a burden to the public health. After heart disease, cancer is the most common cause of death in the United States. In 2008, it was estimated that about 565,650 Americans were expected to die of cancer. Although, the incidence of cancer has been dropping over the years, it was estimated that over 1.4 million Americans would be diagnosed with cancer in 2008.
Cancer is not only a health burden but also a financial burden to the country. The NIH estimated the overall cost of cancer in 2007 to be $219.2 billion dollars with $89 billion attributable to direct medical costs. It is expected that cancer will continue to be a public health problem for the foreseeable future which prompts the need for the development of new therapeutics.
Chemotherapy is still the standard approach for treating cancers even though there were high expectations that targeted therapeutics would become the preferred drugs in cancer treatment. Current topoisomerase inhibitors have demonstrated to be effective chemotherapy drugs and they continue being developed for use in combination therapy with targeted therapeutics. However, top2 inhibitors need to be improved in order to overcome their limitations. A next-generation top2 inhibitor like azatoxins has potential in meeting this need.
The National Institutes of Health holds a substantial portfolio of patents in U.S., Europe, Canada, and Australia which claim compositions of azatoxin and its derivatives, pharmaceutical formulations, and methods of use for chemotherapy.
The portfolio includes the following issued patents:
I. United States Patent No. 5,622,960 entitled “Topoisomerase II inhibitors and therapeutic uses therefor” issued April 22, 1997 (HHS Ref. No. E-119-1992/1-US-01).
II. United States Patent No. 5,747,520 entitled “Topoisomerase II inhibitors and therapeutic uses therefor” issued May 5, 1998 (HHS Ref. No. E-119-1992/1-US-17).
III. European Patent No. 0665846 entitled “Topoisomerase II inhibitors and therapeutic uses therefor” issued July 29, 1998 (HHS Ref. No. E-119-1992/1-EP-10) validated in Austria, Belgium, Denmark, France, Germany, Great Britain, Ireland, Italy, Luxembourg, Switzerland, and The Netherlands.
IV. Canadian Patent No. 2147608 entitled “Topoisomerase II inhibitors and therapeutic uses therefor” issued December 12, 2006 (HHS Ref. No. E-119-1992/1-CA-06).
V. Australian Patent No. 676511 entitled “Topoisomerase II inhibitors and therapeutic uses therefor” issued June 13, 1997 (HHS Ref. No. E-119-1992/1-AU-04).
Next Step: Teleconference
There will be a teleconference where the principal investigator, Dr. Yves Pommier, will explain this technology. Licensing and collaborative research opportunities will also be discussed. If you are interested in participating in this teleconference please call or e-mail Samuel Bish; (301) 435-5282; firstname.lastname@example.org. The NIH Office of Technology Transfer (OTT) will then e-mail you the date, time, and number for the teleconference.Start Signature
Dated: April 16, 2009.
Richard U. Rodriguez,
Director, Division of Technology Development and Transfer, Office of Technology Transfer, National Institutes of Health.
[FR Doc. E9-9344 Filed 4-22-09; 8:45 am]
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