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Mechanisms of the Antiproliferative and Antitumor Activity of Novel Telomerase-Carbonic Anhydrase Dual-Hybrid Inhibitorsстатья
Статья опубликована в высокорейтинговом журнале
Статья опубликована в журнале из списка Web of Science и/или Scopus- Авторы: Plyasova AA, Berrino E., Khan II, Veselovsky AV, Pokrovsky VS, Angeli A., Ferraroni M., Supuran CT, Pokrovskaya MV, Alexandrova SS, Gladilina YA, Sokolov NN, Hilal A., Carta F., Zhdanov DD
- Журнал: Journal of Medicinal Chemistry
- Том: 64
- Номер: 15
- Год издания: 2021
- Издательство: American Chemical Society
- Местоположение издательства: United States
- DOI: 10.1021/acs.jmedchem.1c00756
- Аннотация: 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 7 and 9 suppressed hTL activity in both cell lysates and human colon cancer cell lines, and prolonged incubation with either 7 or 9 resulted in telomere shortening, cell cycle arrest, replicative senescence, and apoptosis. Enzyme kinetics showed that 7 and 9 are 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 9 showed antitumor activity in Colo-205 mouse xenografts and suppressed telomerase activity by telomere reduction.
- Добавил в систему: Покровский Вадим Сергеевич