2. Academic Validation
  3. Destabilizers of the thymidylate synthase homodimer accelerate its proteasomal degradation and inhibit cancer growth

Destabilizers of the thymidylate synthase homodimer accelerate its proteasomal degradation and inhibit cancer growth

  • Elife. 2022 Dec 7:11:e73862. doi: 10.7554/eLife.73862.
Luca Costantino 1,  Stefania Ferrari 1,  Matteo Santucci 1,  Outi M H Salo-Ahen 2,  Emanuele Carosati 3,  Silvia Franchini 1,  Angela Lauriola 4,  Cecilia Pozzi 5,  Matteo Trande 1,  Gaia Gozzi 1,  Puneet Saxena 1,  Giuseppe Cannazza 1,  Lorena Losi 1,  Daniela Cardinale 6,  Alberto Venturelli 1,  Antonio Quotadamo 1,  Pasquale Linciano 1,  Lorenzo Tagliazucchi 1,  Maria Gaetana Moschella 1 7,  Remo Guerrini 8,  Salvatore Pacifico 8,  Rosaria Luciani 1,  Filippo Genovese 1,  Stefan Henrich 2,  Silvia Alboni 1,  Nuno Santarem 9,  Anabela da Silva Cordeiro 9 10,  Elisa Giovannetti 11 12,  Godefridus J Peters 11,  Paolo Pinton 13,  Alessandro Rimessi 13,  Gabriele Cruciani 3,  Robert M Stroud 14,  Rebecca C Wade 2 15 16,  Stefano Mangani 5,  Gaetano Marverti 4,  Domenico D'Arca 4,  Glauco Ponterini 1,  Maria Paola Costi 1
Affiliations

Affiliations

  • 1 Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • 2 Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.
  • 3 Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy.
  • 4 Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • 5 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.
  • 6 Respiratory, Critical Care & Anesthesia UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
  • 7 Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy, Modena, Italy.
  • 8 Department of Chemical and Pharmaceutical Science, University of Ferrara, Ferrara, Italy.
  • 9 IBMC I3S, Porto, Portugal.
  • 10 Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal.
  • 11 Department of Medical Oncology, Amsterdam University Medical Center, Cancer Center Amsterdam, 1081HV, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
  • 12 CancerPharmacology Lab, Fondazione Pisana per la Scienza, Pisa, Italy.
  • 13 Dept. of Medical Sciences and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
  • 14 Biochemistry and Biophysics Department, University of California San Francisco, San Francisco, United States.
  • 15 Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany.
  • 16 Center for Molecular Biology (ZMBH), DKFZ-ZMBH Alliance, Heidelberg University, Heidelberg, Germany.
PMID: 36475542 DOI: 10.7554/eLife.73862
Abstract

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.

Keywords

biochemistry; cancer biology; cancer growth inhibition; chemical biology; enzyme dissociative inhibition mechanism; human; proteasomal degradation; protein dimer destabilizers; target engagement; thymidylate synthase.

Figures
Products