Exploring the chemical space of G-quadruplex binders: Discovery of a novel chemotype targeting the human telomeric sequence

Francesco Saverio Di Leva, Pasquale Zizza, Chiara Cingolani, Carmen D'Angelo, Bruno Pagano, Jussara Amato, Erica Salvati, Claudia Sissi, Odra Pinato, Luciana Marinelli, Andrea Cavalli, Sandro Cosconati, Ettore Novellino, Antonio Randazzo, Annamaria Biroccio

Research output: Contribution to journalArticlepeer-review

Abstract

Recent findings have unambiguously demonstrated that DNA G-rich sequences can adopt a G-quadruplex folding in living cells, thus further validating them as crucial targets for anticancer therapy. Herein, to identify new potent G4 binders as antitumor drug candidates, we have targeted a 24-nt G4-forming telomeric sequence employing a receptor-based virtual screening approach. Among the best candidates, in vitro binding experiments allowed identification of three novel G4 ligands. Among them, the best compound features an unprecedented binding selectivity for the human telomeric DNA G-quadruplex with no detectable binding for other G4-forming sequences present at different genomic sites. This behavior correlates with the detected ability to generate DNA damage response in tumor cells at the telomeric level and efficient antiproliferative effect on different tumor cell lines at low micromolar concentrations.

Original languageEnglish
Pages (from-to)9646-9654
Number of pages9
JournalJournal of Medicinal Chemistry
Volume56
Issue number23
DOIs
Publication statusPublished - Dec 12 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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