All cancerous cells share a single potential vulnerability: they must continually lengthen their telomeres in order to replicate. Most cancers abuse telomerase in order to do this, while a minority use the alternative lengthening of telomeres (ALT) mechanisms. Normally, in humans, telomerase is only present in stem cell populations, those that must maintain themselves across a life span. It is not present in somatic cells, the vast majority of any tissue. The primary activity of telomerase is to extend the repeated DNA sequences known as telomeres, found at the ends of chromosomes. Telomeres are a part of the mechanism by which somatic cells are limited in the number of times they can divide; a little of the telomere length is lost with each cell division, and when telomeres are short, cells self-destruct or become senescent.
Thus in any normal tissue, only a small population of stem cells is privileged to replicate more or less indefinitely. These cells generate daughter somatic cells that have a finite lifetime. This structure is the way in which higher life forms have evolved to reduce the risk of cancer to a sufficiently low level. Cancer arises due to random mutations that enable cells to replicate uncontrollably, and that must, by necessity, include a way to lengthen telomeres. Having the majority of cells in the body limited in life span, reduces the risk of any given cell accumulating the right collection of mutations to trigger cancer.
When looking at progress towards the medical control of cancer, the most efficient way forward is to focus on targeting mechanisms that are shared by all cancers, or at least by a very large subset of cancers. The most economical way forward is to find a class of therapy that can be applied to many cancers with minimal adjustment – there are hundreds of varieties of cancer, and only so many researchers and only so much funding for research. The best of the potential approaches that are presently known is to find some way to interfere in telomere lengthening. This is why the research materials here are interesting: any viable way to suppress telomerase activity is one sizable portion of a universal cancer therapy.
Researcher have developed a promising molecular tool that targets and inhibits one of cell immortality’s underlying gears: the enzyme telomerase. This enzyme is found overexpressed in approximately 90% of human cancer cells and has become an important subject of study for cancer researchers. Normal cells have the gene for telomerase, but it typically is not expressed. “Telomerase is the primary enzyme that allows cancer cells to live forever. We want to short-circuit this immortality. Now we have designed a first-of-its-kind small molecule that irreversibly binds to telomerase, shutting down its activity. This mechanism offers a new pathway for treating cancer and understanding cellular aging.”
The big idea for the small molecule design came from nature. A decade ago, the researchers were intrigued by the biological activity of chrolactomycin, which is produced by bacteria and has been shown to inhibit telomerase. The team used chrolactomycin as a starting point in the design of their small molecules. They produced more than 200 compounds over the years, and the compound they call NU-1 was the most effective of those tested. Its synthesis is very efficient, taking fewer than five steps. “NU-1 inhibits telomerase unlike anything that came before it. It does this by forming a covalent bond. Another advantage of NU-1 is that its molecular structure should enable scientists to add cargo, such as a therapeutic.”
Telomerase is a ribonuceloprotein complex responsible for maintaining telomeres and protecting chromosomal integrity. The human telomerase reverse transcriptase (hTERT) is expressed in ∼90% of cancer cells where it confers the capacity for limitless proliferation. Along with its established role in telomere lengthening, telomerase also serves noncanonical extra-telomeric roles in oncogenic signaling, resistance to apoptosis, and enhanced DNA damage response. We report a new class of natural-product-inspired covalent inhibitors of telomerase that target the catalytic active site.