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Disrupters of the Thymidylate Synthase Homodimer Accelerate Its Proteasomal Degradation and Inhibit Cancer Growth.

submitted on 04.03.2021, 00:33 and posted on 08.03.2021, 04:57 by Costantino Luca, Stefania Ferrari, Matteo Santucci, Outi M. Salo-Ahen, Carosati Emanuele, Silvia Franchini, Lauriola Angela, Cecilia Pozzi, Gaetano Marverti, Matteo Trande, Gozzi Gaia, Puneet Saxena, Giuseppe Cannazza, Lorena Losi, Daniela Cardinale, Alberto Venturelli, Antonio Quotadamo, Pasquale Linciano, Remo Guerrini, Salvatore Pacifico, Rosaria Luciani, Filippo Genovese, Henrich Stefan, Alboni Silvia, Nuno Santarem, Anabela Cordeiro-da-Silva, Elisa Giovannetti, Godefridus Peters, Paolo Pinton, Alessandro Rimessi, Gabriele Cruciani, Robert Stroud, Rebecca Wade, Stefano Mangani, Domenico D'Arca, Glauco Ponterini, Maria Paola Costi

Drugs that target human thymidylate synthase (hTS) are widely used in anti-cancer therapy. However, treatment with classical substrate-site-directed TS inhibitors induces its over-expression and the development of drug resistance. We thus pursued an alternative strategy that led to the discovery of TS-dimer disrupters that bind at the monomer-monomer interface and shift the dimerization equilibrium of both the recombinant and the intracellular protein toward the inactive monomers. We performed a structural, spectroscopic and kinetic investigation of the effects of these small molecules andthe best one, E7, accelerates the proteasomal degradation of hTS in cancer cells. E7 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.


AIRC, IG16977

European Union 6 STREP: LSH- 2005-2.2.0-8, 037852

CCA foundation grants-2012/2015 CCA2015-1-19

AIRC 14422

NIH GM24485

Finnish Cultural Foundation, the Academy of Finland (137918)

AIRC, IG 23670

PRIN Grant 2017E5L5P3


PRIN, Grant 2017XA5J5N


Email Address of Submitting Author


University of Modena and Reggio Emilia



ORCID For Submitting Author


Declaration of Conflict of Interest

No conflict of interest