| Autor: |
Luca Costantino, Stefania Ferrari, Matteo Santucci, Outi MH Salo-Ahen, Emanuele Carosati, Silvia Franchini, Angela Lauriola, Cecilia Pozzi, Matteo Trande, Gaia Gozzi, Puneet Saxena, Giuseppe Cannazza, Lorena Losi, Daniela Cardinale, Alberto Venturelli, Antonio Quotadamo, Pasquale Linciano, Lorenzo Tagliazucchi, Maria Gaetana Moschella, Remo Guerrini, Salvatore Pacifico, Rosaria Luciani, Filippo Genovese, Stefan Henrich, Silvia Alboni, Nuno Santarem, Anabela da Silva Cordeiro, Elisa Giovannetti, Godefridus J Peters, Paolo Pinton, Alessandro Rimessi, Gabriele Cruciani, Robert M Stroud, Rebecca C Wade, Stefano Mangani, Gaetano Marverti, Domenico D'Arca, Glauco Ponterini, Maria Paola Costi |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
eLife, Vol 11 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
2050-084X |
| DOI: |
10.7554/eLife.73862 |
| Popis: |
Drugs that target human thymidylate synthase (hTS), a dimeric enzyme, are widely used in anticancer therapy. However, treatment with classical substrate-site-directed TS inhibitors induces over-expression of this protein and development of drug resistance. We thus pursued an alternative strategy that led us to the discovery of TS-dimer destabilizers. These compounds bind at the monomer-monomer interface and shift the dimerization equilibrium of both the recombinant and the intracellular protein toward the inactive monomers. A structural, spectroscopic, and kinetic investigation has provided evidence and quantitative information on the effects of the interaction of these small molecules with hTS. Focusing on the best among them, E7, we have shown that it inhibits hTS in cancer cells and accelerates its proteasomal degradation, thus causing a decrease in the enzyme intracellular level. E7 also showed a superior anticancer profile to fluorouracil in a mouse model of human pancreatic and ovarian cancer. Thus, over sixty years after the discovery of the first TS prodrug inhibitor, fluorouracil, E7 breaks the link between TS inhibition and enhanced expression in response, providing a strategy to fight drug-resistant cancers. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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