Graduate Student Leah Knepper

"Anti-Cancer Effects of Targeting Telomeric DNA and the Telomerase Enzyme"

One of the defining hallmarks of cancer is replicative immortality as a result of telomerase activity.1 As cells in healthy tissue replicate, they experience gradual shortening of their telomeres—the protective structure at chromosome ends.2 Telomeres eventually reach a critical length that triggers cellular senescence.3 This process is a defense against DNA damage but is circumvented in over 90% of tumors.2 Thus, telomeric DNA and telomerase activity in cancer cells is a promising target for cancer therapeutics.

Yu et al. created artificial nucleases capable of binding telomeric DNA and cleaving it directly to shorten chromosome ends, as telomerase prevents natural sequence shortening in cancer cells.4 The G-rich telomeric repeats form G-quadruplex structures which can be bound by the artificial nuclease core, while DNA is cleaved by amino terminal Cu(II)- and Ni(II)-binding (ATCUN) motifs. These artificial nucleases were taken up in cells and were observed localizing in the nucleus; compounds also reduced telomere length in cancer cells.

Berrino et al. and Plyasova et al. explore the use of carbonic anhydrase-telomerase dual inhibitors.5,6 Traditional telomerase inhibitors have been associated with toxicity risks as well as delayed effect after treatment. Tumor-associated carbonic anhydrase IX and XII are targeted along with telomerase in these single-molecule dual inhibitors. These inhibitors exhibit concentration-dependent inhibition of telomerase activity and increase apoptosis and cell death in cell culture. One was found to reduce tumor size in mice as well as decrease telomerase activity and reduce telomere length in vivo.

1. Hanahan, D.; Weinberg, R. Hallmarks of Cancer: The Next Generation. Cell 2011, 144, 646-674.
2. Srinivas, N.; Rachakonda, S.; Kumar, R. Telomeres and Telomere Length: A General Overview. Cancers 2020, 12, 558.
3. Chakravarti, D.; LaBella, K. A.; DePinho, R. A. Telomeres: history, health, and hallmarks of aging. Cell 2021, 184, 306-322.
4. Yu, Z., et al. Rapid Telomere Reduction in Cancer Cells Induced by G Quadruplex-Targeting Copper Complexes. Journal of medicinal chemistry 2019, 62, 5040-5048.
5. Berrino, E., et al. Azidothymidine “Clicked” into 1,2,3-Triazoles: First Report on Carbonic Anhydrase–Telomerase Dual-Hybrid Inhibitors. J. Med. Chem. 2020, 63, 7392.
6. Plyasova, A. A., et al. Mechanisms of the Antiproliferative and Antitumor Activity of Novel Telomerase–Carbonic Anhydrase Dual-Hybrid Inhibitors. J. Med. Chem. 2021, 64, 11432.