TY - JOUR
T1 - Destabilizers of the thymidylate synthase homodimer accelerate its proteasomal degradation and inhibit cancer growth
AU - Costantino, Luca
AU - Ferrari, Stefania
AU - Santucci, Matteo
AU - Salo-Ahen, Outi M. H.
AU - Carosati, Emanuele
AU - Franchini, Silvia
AU - Lauriola, Angela
AU - Pozzi, Cecilia
AU - Trande, Matteo
AU - Gozzi, Gaia
AU - Saxena, Puneet
AU - Cannazza, Giuseppe
AU - Losi, Lorena
AU - Cardinale, Daniela
AU - Venturelli, Alberto
AU - Quotadamo, Antonio
AU - Linciano, Pasquale
AU - Tagliazucchi, Lorenzo
AU - Moschella, Maria Gaetana
AU - Guerrini, Remo
AU - Pacifico, Salvatore
AU - Luciani, Rosaria
AU - Genovese, Filippo
AU - Henrich, Stefan
AU - Alboni, Silvia
AU - Santarem, Nuno
AU - da Silva Cordeiro, Anabela
AU - Giovannetti, Elisa
AU - Peters, Godefridus J.
AU - Pinton, Paolo
AU - Rimessi, Alessandro
AU - Cruciani, Gabriele
AU - Stroud, Robert M.
AU - Wade, Rebecca C.
AU - Mangani, Stefano
AU - Marverti, Gaetano
AU - D'Arca, Domenico
AU - Ponterini, Glauco
AU - Costi, Maria Paola
N1 - Funding Information: This work was funded by AIRC2015 IG16977 (MPC), European Union (LIGHTS-A Framework 6 STREP: LSH-2005–2.2.0-8) Grant agreement n°037852 to MPC, RCW, GC, RMS; CCA foundation grants-2012/2015 CCA2015-1-19 to EG and GJP, AIRC 14422 Start-Up grant to EG, the Klaus Tschira Foundation (RCW, SH, OMHS-A) and the Alexander von Humboldt Foundation, the Finnish Cultural Foundation, the Academy of Finland (137918), and the University of Eastern Finland (OMHS-A). RMS is supported by NIH GM24485. PP is supported by Italian Association for Cancer Research (AIRC, IG23670). AR is supported by the Italian Ministry of Health (GR-2016–02364602) and by the Italian Ministry of Education, University and Research (PRIN, Grant 2017XA5J5N). Funding Information: We thank Dr. Hannu Myllykallio for cloning hTS and preparing bacterial cells expressing mutant proteins, and Dr. Amir Avan and Dr. Niccola Funel for their work on PDAC animal models and staining. The authors also acknowledge the ‘Fondazione Cassa di Risparmio di Modena’ for funding the UHPLC-ESI-QTOF system at the Centro Interdipartimentale Grandi Strumenti (CIGS). PP is grateful to Camilla degli Scrovegni for continuous inspirational support. Publisher Copyright: © Costantino et al.
PY - 2022/12/7
Y1 - 2022/12/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85145968091&partnerID=8YFLogxK
U2 - https://doi.org/10.7554/eLife.73862
DO - https://doi.org/10.7554/eLife.73862
M3 - Article
C2 - 36475542
SN - 2050-084X
VL - 11
JO - eLife
JF - eLife
M1 - e73862
ER -