A G-Quadruplex DNA Cleaving Compound and Novel DNA-Cleaving Antitumor Agents
Background There have been few dramatic therapeutic breakthroughs in cancer research. More anticancer drugs are in use today than ever before, but nearly all of these drugs are severely limited in their use, due to the dual problems of drug resistance and lack of selectivity. The guanine-rich ends of chromosomes, the telomeres, are prime targets for anticancer agents. The DNA in these regions of the genome are believed to be capable of forming G-quadruplex structures, yet no known compound exists that might recognize and selectively cleave these unique DNA structures. It is postulated that G-quadruplex structures are more prevalent in cancer cells than normal cells, providing a means of selectivity in treatment.
Invention Description This invention describes a new compound that selectively cleaves G-quadruplex DNA. This compound may have applications in the treatment of cancer and other proliferative diseases. We show that compound I is selective for G-quadruplex DNA and leaves duplex DNA relatively unharmed. A significant advantage of this compound from the therapeutic point of view is that water-soluble sodium salts of this compound can be readily formulated.
A method for treating cancer involving the use of novel compounds is described and claimed as new compositions of matter. The utility of these compounds for the treatment of cancer stems from the way that they interact with DNA. These compounds are non-hydrolyzable, cationic compounds that bind to DNA. They also undergo a series of chemical reactions in the presence of DNA to generate reactive intermediates that cleave the DNA. These compounds may selectively localize to cancer cells due to their lipophilic, cationic nature. Thus, these compounds are exciting new candidates for cancer therapeutic treatment.
These drugs are readily taken up by cancer cells. Importantly, these compounds cleave DNA structures prevalent in cancer cells. High selectivity allows exposure of cells and animals to compounds with little toxicity concerns.
New anticancer drug compositions Can be refined through high-throughput screening Cancer cells are affected by specific interactions with DNA structures prevalent in telomeric domains
Market Potential/Applications Cancer is the second leading cause of death in the United States. Each year, over half a million Americans die from cancer. The global cancer market is predicted to be around $20 billion in 2004, and is expected to increase to over $45 billion by 2011. Over the next decade, advances in the pharmacotherapy of cancer will come not only from improvements in the traditional classes of therapies, but also from introduction of innovative therapies such as this one, that display improved efficacy and toxicity through a targeted approach.
Development Stage Proof of concept
IP Status 11 foreign patent application filed
UT Researcher Sean M. Kerwin, Ph.D., College of Pharmacy, The University of Texas at Austin Wendi M. David, Ph.D., Chemistry and Biochemistry, The University of Texas at Austin
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