Telomerase is the RNA-protein enzyme complex that lengthens telomeres, thereby conferring cellular immortality to ~90% of all cancers, including many paediatric cancers. Because telomerase is undetectable in most normal tissues, telomerase is a prime therapeutic target of exceptionally broad scope through the application of telomerase inhibitors. However, no small-molecule telomerase inhibitors have entered clinical trials.
We have developed a small-molecule telomerase inhibitor that abolishes activity at the low-nanomolar level (IC50 ≤ 5 nM). We have achieved a cryo-EM structure of the catalytic lobe of human telomerase to ~2.4 Angstrom; this is enabling us to further refine potency and specificity of the telomerase inhibitor through structure-based drug design, by acquiring cryo-EM data on the complex of [telomerase + inhibitor].
Furthermore, research from our labs has revealed an interdependence between telomerase action at telomeres and the DNA damage & replication stress response. Given that many standard-of-care chemotherapeutic agents cause DNA damage and/or replication stress, we hypothesise that this interdependence can be exploited to identify and mechanistically define synergistic combinations of telomerase inhibitor with chemotherapeutic agents.