New Telomerase Inhibitors as Possible Anticancer Treatments
Life Sciences : Therapeutics
Available for licensing
- Sean Kerwin, Ph.D. , College of Pharmacy
- Shih-Fong Chen, Ph.D. , Cancer Therapy & Research Center
- Ira Maine, Ph.D. , Cancer Therapy & Research Center
- Terace Fletcher, Ph.D. , Cancer Therapy & Research Center
- Miguel Salazar, Ph.D. , College of Pharmacy
- Blain Mamiya, Ph.D. , Pharmacy
- Bradford Windle, Ph.D. , Cancer Therapy & Research Center
- Makoto Wajima, Ph.D. , Cancer Therapy & Research Center
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 conventional therapy.
However, there are also several potential limitations of telomerase inhibition as a therapeutic strategy. For example, there is a lag phase between telomerase inhibition and telomere shortening, with growth arrest and cell death.
The inventors from The University of Texas at Austin 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.
- A simpler substrate for the design and production of anticancer treatments
- Useful for treating proliferate diseases
- Provides a non-nucleoside inhibitor of telomerase
- Mediating allosteric-like inhibition of telomerase
- Premature termination and shortening of telomeric DNA
- Destabilization of telomeric structure and function
Novel substrate for modulation of human telomerase
These new telomerase inhibitors could play a 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 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.
Proof of concept