Inhibitor of ovarian cancer cells growth by virtual screening: a new thiazole derivative targeting human thymidylate synthase

  • J Med Chem. 2012 Nov 26;55(22):10272-6. doi: 10.1021/jm300850v.
Emanuele Carosati  1 ,  Anna Tochowicz ,  Gaetano Marverti ,  Giambattista Guaitoli ,  Paolo Benedetti ,  Stefania Ferrari ,  Robert M Stroud ,  Janet Finer-Moore ,  Rosaria Luciani ,  Davide Farina ,  Gabriele Cruciani ,  M Paola Costi
Affiliations
  • 1. Dipartimento di Chimica, Università degli Studi di Perugia , Via Elce di Sotto 10, 06123, Perugia, Italy.
PMID: 23075414 DOI: 10.1021/jm300850v
Abstract

Human Thymidylate Synthase (hTS) was targeted through a virtual screening approach. The most optimal inhibitor identified, 2-{4-hydroxy-2-[(2-hydroxybenzylidene)hydrazono]-2,5-dihydrothiazol-5-yl}-N-(3-trifluoromethylphenyl)acetamide (5), showed a mixed-type inhibition pattern, with a K(i) of 1.3 μM and activity against ovarian Cancer cell lines with the same potency as cisplatin. X-ray studies revealed that it binds the inactive enzyme conformation. This study is the first example of a nonpeptidic inhibitor that binds the inactive hTS and exhibits Anticancer activity against ovarian Cancer cells.