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Destabilizers of the thymidylate synthase homodimer accelerate its proteasomal degradation and inhibit cancer growth.
Costantino, Luca; Ferrari, Stefania; Santucci, Matteo; Salo-Ahen, Outi M H; Carosati, Emanuele; Franchini, Silvia; Lauriola, Angela; Pozzi, Cecilia; Trande, Matteo; Gozzi, Gaia; Saxena, Puneet; Cannazza, Giuseppe; Losi, Lorena; Cardinale, Daniela; Venturelli, Alberto; Quotadamo, Antonio; Linciano, Pasquale; Tagliazucchi, Lorenzo; Moschella, Maria Gaetana; Guerrini, Remo; Pacifico, Salvatore; Luciani, Rosaria; Genovese, Filippo; Henrich, Stefan; Alboni, Silvia; Santarem, Nuno; da Silva Cordeiro, Anabela; Giovannetti, Elisa; Peters, Godefridus J; Pinton, Paolo; Rimessi, Alessandro; Cruciani, Gabriele; Stroud, Robert M; Wade, Rebecca C; Mangani, Stefano; Marverti, Gaetano; D'Arca, Domenico; Ponterini, Glauco; Costi, Maria Paola.
Afiliación
  • Costantino L; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • Ferrari S; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • Santucci M; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • Salo-Ahen OMH; Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.
  • Carosati E; Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy.
  • Franchini S; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • Lauriola A; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • Pozzi C; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.
  • Trande M; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • Gozzi G; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • Saxena P; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • Cannazza G; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • Losi L; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • Cardinale D; Respiratory, Critical Care & Anesthesia UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
  • Venturelli A; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • Quotadamo A; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • Linciano P; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • Tagliazucchi L; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • Moschella MG; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • Guerrini R; Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy, Modena, Italy.
  • Pacifico S; Department of Chemical and Pharmaceutical Science, University of Ferrara, Ferrara, Italy.
  • Luciani R; Department of Chemical and Pharmaceutical Science, University of Ferrara, Ferrara, Italy.
  • Genovese F; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • Henrich S; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • Alboni S; Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.
  • Santarem N; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • da Silva Cordeiro A; IBMC I3S, Porto, Portugal.
  • Giovannetti E; IBMC I3S, Porto, Portugal.
  • Peters GJ; Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal.
  • Pinton P; Department of Medical Oncology, Amsterdam University Medical Center, Cancer Center Amsterdam, 1081HV, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
  • Rimessi A; CancerPharmacology Lab, Fondazione Pisana per la Scienza, Pisa, Italy.
  • Cruciani G; Department of Medical Oncology, Amsterdam University Medical Center, Cancer Center Amsterdam, 1081HV, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
  • Stroud RM; Dept. of Medical Sciences and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
  • Wade RC; Dept. of Medical Sciences and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
  • Mangani S; Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy.
  • Marverti G; Biochemistry and Biophysics Department, University of California San Francisco, San Francisco, United States.
  • D'Arca D; Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.
  • Ponterini G; Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany.
  • Costi MP; Center for Molecular Biology (ZMBH), DKFZ-ZMBH Alliance, Heidelberg University, Heidelberg, Germany.
Elife ; 112022 12 07.
Article en En | MEDLINE | ID: mdl-36475542
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Timidilato Sintasa Límite: Animals / Female / Humans Idioma: En Revista: Elife Año: 2022 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
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PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Timidilato Sintasa Límite: Animals / Female / Humans Idioma: En Revista: Elife Año: 2022 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido