Telomere-targeting anticancer drugs

In normal somatic cells, telomere length decreases with each replication event, until a critical state of replicative senescence is reached. On the contrary, telomere maintenance is evident in all types of cancer cells. 85% of them manage in doing so by upregulating expression of telomerase, while the remaining have a mechanism that involves recombination events between telomeres, known as alternative lengthening of telomere (ALT). In all cases, telomeres are maintained at a length above a critical threshold, and this in turn permits unlimited replication of cancer cells. Accordingly, treatments preventing telomere lengthening are potentially a major and effective strategy for the anticancer therapy. In human cells, telomeric DNA is composed of tandem repeats of the sequence d(TTAGGG) with a 3′ single-stranded extension that may fold into an unusual four-stranded helical structure named G-quadruplex. Since small organic molecules able to bind G-quadruplexes have been shown to alter telomere functions, leading to marked inhibition of tumour cells growth, the telomeres represent an extremely attractive target for cancer therapy. The most striking problem limiting this scenario is the scarce selectivity found in the majority of known G-quadruplex targeting ligands, typically exhibiting also remarkable toxicity as a consequence of unspecific binding. To the best of our knowledge, fast and simple analytical methods allowing to unambiguously identify new anticancer agents, exclusively recognizing with high binding affinity telomeric DNA quadruplex, are lacking. In this context, the development of a novel strategy to discover ligands able to exclusively recognize G-quadruplex tracts while discriminating double stranded DNA is strongly called for. In this frame, we here propose the development of an innovative methodology enabling a rapid and efficient identification of specific telomeric G-quadruplex-binding ligands. Secondly, we intend to employ this methodology in the screening of focused libraries of novel, different G-quadruplex-binding agents designed on the basis of known lead compounds, so to obtain potential anticancer drugs with enhanced activity/toxicity ratio. Finally, the biological activity of the drugs exhibiting the highest affinities for the target telomeric structures will be tested on a panel of human tumor cell lines of different histotypes.