TY - JOUR
T1 - Exploring the chemical space of G-quadruplex binders
T2 - Discovery of a novel chemotype targeting the human telomeric sequence
AU - Di Leva, Francesco Saverio
AU - Zizza, Pasquale
AU - Cingolani, Chiara
AU - D'Angelo, Carmen
AU - Pagano, Bruno
AU - Amato, Jussara
AU - Salvati, Erica
AU - Sissi, Claudia
AU - Pinato, Odra
AU - Marinelli, Luciana
AU - Cavalli, Andrea
AU - Cosconati, Sandro
AU - Novellino, Ettore
AU - Randazzo, Antonio
AU - Biroccio, Annamaria
PY - 2013/12/12
Y1 - 2013/12/12
N2 - 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.
AB - 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.
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U2 - 10.1021/jm401185b
DO - 10.1021/jm401185b
M3 - Article
AN - SCOPUS:84890516811
VL - 56
SP - 9646
EP - 9654
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 23
ER -