New Telomerase Inhibitors as Possible Anticancer Treatments
Introduction
Most tumor cells have high expression of telomerase, whereas most normal somatic cells express low or undetectable levels of telomerase. Continued proliferation of tumor cells requires activation of telomerase to maintain chromosomal stability and to extend life span, because telomerase elongates telomere length and rewinds the cellular mitotic clock. Conversely, shortening of telomeres by inhibition of telomerase activity induces growth arrest (senescence) and apoptosis in tumor cells. Moreover, it has been reported that inhibition of telomerase increases the susceptibility of tumor cells to apoptosis induced by anticancer agents. Thus, telomerase inhibitors could be used as an adjuvant with conven tional therapy. However, there are also several potential limitations of telomerase inhibition as a thera peutic strategy. For example, there is a lag phase between telomerase inhibition and telomere shortening, with growth arrest and cell death.
Invention Description
It was found that normal human stem cells produce a regulated non-processive telomerase activity, while cancer cells produce a processive telomerase activity. Nucleotide analogs, such as 7-deaza-2'-deoxyquanosine-5'-triphosphate (7-deaza-dGTP) were found to be substrates for processive telomerase and incorporated into telomeric sequence. The incorporation of this nucleotide subsequently affected the processivity of telomerase, converting processive telomerase to non-processive telomerase. The incorporation of this nucleotide analog was also found to inhibit formation of G-quartets by telomeric sequence. Understanding the mechanisms of telomerase modulation by the 7-deazanucleotides has allowed the design of new telomerase inhibitors, modulators and agents for affecting telomere structure and function. The finding of 85%-90% telomerase has been extended to a wide range of tumors.
Benefits
- A simpler substrate for the design and production of new anticancer treatments
- Useful for treating proliferate diseases
- Specificity with interaction to DNA structures
- Provide a non-nucleoside inhibitors of telomerase
Features
- Mediating allosteric-like inhibition of telomerase
- Premature termination and shortening of telomeric DNA
- Destabilization of telomeric structure and function
Market Potential/Applications
These new telomerase inhibitors could play a huge role in the multibillion-dollar markets for the treatment of cancer. 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 worth 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 completed.
IP Status
U.S. Patent Issued: 6,004,939
U.S. Patent Issued: 6,054,442
U.S. Patent Issued: 6,593,306
PCT Application filed
UT Researcher
Sean Kerwin, Ph.D., College of Pharmacy, The University of Texas at Austin
For further information please contact
University of Texas,
Austin, USA
Website : www.otc.utexas.edu
