학술논문
Mechanisms of the Antiproliferative and Antitumor Activity of Novel Telomerase–Carbonic Anhydrase Dual-Hybrid Inhibitors
Document Type
Article
Author
Plyasova, Anna A.; Berrino, Emanuela; Khan, Irina I.; Veselovsky, Alexander V.; Pokrovsky, Vadim S.; Angeli, Andrea; Ferraroni, Marta; Supuran, Claudiu T.; Pokrovskaya, Marina V.; Alexandrova, Svetlana S.; Gladilina, Yulia A.; Sokolov, Nikolay N.; Hilal, Abdullah; Carta, Fabrizio; Zhdanov, Dmitry D.
Source
Journal of Medicinal Chemistry; August 2021, Vol. 64 Issue: 15 p11432-11444, 13p
Subject
Language
ISSN
00222623; 15204804
Abstract
Human (h) telomerase (TL; EC 2.7.7.49) plays a key role in sustaining cancer cells by means of elongating telomeric repeats at the 3′ ends of chromosomes. Since TL-inhibitor (TI) stand-alone cancer therapy has been proven to be remarkably challenging, a polypharmacological approach represents a valid alternative. Here we consider a series of compounds able to inhibit both hTL and the tumor-associated carbonic anhydrases (CAs; EC 4.2.1.1) IX and XII. Compounds 7and 9suppressed hTL activity in both cell lysates and human colon cancer cell lines, and prolonged incubation with either 7or 9resulted in telomere shortening, cell cycle arrest, replicative senescence, and apoptosis. Enzyme kinetics showed that 7and 9are mixed-type inhibitors of the binding of DNA primers and deoxynucleoside triphosphate (dNTP) to the TL catalytic subunit hTERT, which is in agreement with docking experiments. Compound 9showed antitumor activity in Colo-205 mouse xenografts and suppressed telomerase activity by telomere reduction.