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
