Breaking cancer cells immortality

Cancer cells growth relies on molecular mechanisms that make them immortal. Multiple crucial enzymes involved in tumors survival can be blocked by the same drugs, as shown from XRD2 structural data.

(Ref: Berrino E. et al, J.Med.Chem., 63(13), 7392–7409 (2020))

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 KI), 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.
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Azidothymidine (AZT) “clicked” into 1,2,3-Triazoles: First Report on Carbonic Anhydrase-Telomerase Dual Hybrid Inhibitors,
Emanuela Berrino, Andrea Angeli, Dmitry D. Zhdanov, Anna Pavlovna Kiryukhina, Andrea Milaneschi, Alessandro De Luca, Murat Bozdag, Simone Carradori, Silvia Selleri, Gianluca Bartolucci, Thomas S. Peat, Marta Ferraroni, Claudiu T. Supuran, and Fabrizio Carta
J. Medicinal Chemistry 2020 63(13), 7392–7409, doi: 10.1021/acs.jmedchem.0c00636, PDB: 6YPW, 6WKA
Last Updated on Tuesday, 14 July 2020 09:28