Mechanisms of the Antiproliferative and Antitumor Activity of Novel Telomerase-Carbonic Anhydrase Dual-Hybrid Inhibitors.
Anna A PlyasovaEmanuela BerrinoIrina I KhanAlexander V VeselovskyVadim S PokrovskyAndrea AgeliMarta FerraroniClaudiu T SupuranMarina V PokrovskayaSvetlana S AlexandrovaYulia A GladilinaNikolay N SokolovAbdullah HilalFabrizio CartaDmitry D ZhdanovPublished in: Journal of medicinal chemistry (2021)
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.
Keyphrases
- cell cycle arrest
- endothelial cells
- cell death
- cancer therapy
- pi k akt
- induced pluripotent stem cells
- pluripotent stem cells
- drug delivery
- crispr cas
- dna damage
- molecular dynamics simulations
- endoplasmic reticulum stress
- circulating tumor
- stem cells
- bone marrow
- genome editing
- mesenchymal stem cells
- cell therapy
- dna damage response
- aqueous solution
- dna repair