Breaking cancer cells immortality

Cancer cells activate molecular pathways to promote cellular immortality, overexpressing different enzymes, like telomerase (T). Telomerase inhibitors (e.g. azidothymidine-AZT) can represent promising antitumor agents, although they usually are high toxic when administered alone. Better outcomes were observed within a multi pharmacological approach instead. In this context we exploited the validated antitumor targets Carbonic Anhydrases IX and XII (CAs) to attain the first proof of concept on CA-T dual hybrid inhibitors. Novel AZT like compounds have been prepared and showed good in vitro inhibition potency against the CAs IX and XII (low nanomolar range K_I), and strong antitelomerase activity in PC-3 and HT-29 cell lines (IC₅₀ values < 10 uM). High resolution XRD on model hCA II-inhibitor complexes allowed to determine binding modes and thus to set the structural determinants necessary for further development of compounds selectively targeting the tumoral cells.