For the first time, a team of scientists has demonstrated how a small molecule drug binds to a specific pocket of an enzyme activated in approximately 90 percent of all cancers
While there is no "universal" target in cancer, the enzyme telomerase comes close, since it is activated in an overwhelming majority of tumors. Despite the critical role of telomerase in cancer, there are no therapies that target this enzyme in the clinic. In particular, the research and development of small molecule inhibitors of telomerase has been far behind any other approaches due to the lack of available structural information. Structure-based drug design is a powerful tool for the development of inhibitors that are highly potent and specific, characteristics that eliminate the negative side effects usually associated with current chemotherapies.
New research from The Wistar Institute shows exactly how a known, highly selective small molecule telomerase inhibitor is able to bind with the enzyme, thus opening the possibility of developing more telomerase inhibitors that target this pocket of telomerase and could be clinically effective in a wide variety of cancer types.
The findings were published online by the journal Structure.
Telomerase is critical during development because it promotes cell proliferation by allowing cells to overcome their Hayflick limit, or the number of times a population of cells will divide until cell division stops. However, telomerase is switched off in adults and other instances where tissue growth, and therefore cell division, is no longer required to prevent genomic instability in non-proliferating normal cells.
Since unchecked cell division is a hallmark of cancer, it's not surprising that cancer cells reactivate telomerase as a means of proliferating. This reactivation happens in approximately 90 percent of cancers, making telomerase an ideal target. Though small molecule inhibitors that target telomerase have been developed in the past, the precise mechanism of action for any of these inhibitors has been unclear. Moreover, efforts to improve the effectiveness of these compounds against telomerase via chemical modifications have been hindered by the lack of structural data.
"Up until this point, determining how a small molecule inhibitor could halt the ability of telomerase to promote cell division was like having the lock but not knowing which key to use," said Emmanuel Skordalakes, Ph.D., associate professor in the Gene Expression and Regulation Program at The Wistar Institute and lead author of the study. "With this study, we've determined exactly how the key is supposed to fit in the lock."
Skordalakes and his colleagues focused their research on telomerase reverse transcriptase (TERT), a key subunit of telomerase that is divided into four distinct domains: the RNA-binding domain (TRBD), fingers, palm, and thumb.
The scientists found that an experimental telomerase inhibitor called BIBR1532 bound itself to a pocket on the outer surface of the thumb domain of telomerase. The authors also showed that blocking this pocket prevents telomerase from properly assembling, leading to a partially active enzyme, telomere shortening and chromosome uncapping. When this happens, cancer cells are forced into proliferative arrest and senescence - a dormant state - in order to prevent genomic instability.
"Telomerase inhibitors have been studied extensively, yet the mechanism of action of small molecule inhibitors has been difficult to elucidate because of the absence of telomerase structural data," Skordalakes said. "This is the first time a telomerase inhibitor bound to telomerase has been published, and our hope is that our lab and many others can use these findings to develop better telomerase inhibitors that can one day become clinically available for cancer treatment."