G-quadruplex stabilizers are an established opportunity in anticancer chemotherapy. To circumvent the antiproliferative effects of G4 ligands, cancer cells recruit PARP enzymes at telomeres. Herein, starting from the structural similarity of a potent G4 ligand previously discovered by our group and a congeneric PARP inhibitor, a library of derivatives was synthesized to discover the first dual G4/PARP ligand. We demonstrate that a properly decorated thieno[3,2-c]quinolin-4(5H)-one stabilizes the G4 fold in vitro and in cells, induces a DNA damage response localized to telomeres, inhibits PARylation in cells, and has an antiproliferative effect in BRCA2 deficient tumor cells.

Salvati, E., Botta, L., Amato, J., Di Leva, F., Zizza, P., Gioiello, A., et al. (2017). Lead Discovery of Dual G-Quadruplex Stabilizers and Poly(ADP-ribose) Polymerases (PARPs) Inhibitors: A New Avenue in Anticancer Treatment. JOURNAL OF MEDICINAL CHEMISTRY, 60(9), 3626-3635 [10.1021/acs.jmedchem.6b01563].

Lead Discovery of Dual G-Quadruplex Stabilizers and Poly(ADP-ribose) Polymerases (PARPs) Inhibitors: A New Avenue in Anticancer Treatment

Botta, L;GRAZIANI, GRAZIA;
2017-01-01

Abstract

G-quadruplex stabilizers are an established opportunity in anticancer chemotherapy. To circumvent the antiproliferative effects of G4 ligands, cancer cells recruit PARP enzymes at telomeres. Herein, starting from the structural similarity of a potent G4 ligand previously discovered by our group and a congeneric PARP inhibitor, a library of derivatives was synthesized to discover the first dual G4/PARP ligand. We demonstrate that a properly decorated thieno[3,2-c]quinolin-4(5H)-one stabilizes the G4 fold in vitro and in cells, induces a DNA damage response localized to telomeres, inhibits PARylation in cells, and has an antiproliferative effect in BRCA2 deficient tumor cells.
2017
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/14 - FARMACOLOGIA
English
Con Impact Factor ISI
Salvati, E., Botta, L., Amato, J., Di Leva, F., Zizza, P., Gioiello, A., et al. (2017). Lead Discovery of Dual G-Quadruplex Stabilizers and Poly(ADP-ribose) Polymerases (PARPs) Inhibitors: A New Avenue in Anticancer Treatment. JOURNAL OF MEDICINAL CHEMISTRY, 60(9), 3626-3635 [10.1021/acs.jmedchem.6b01563].
Salvati, E; Botta, L; Amato, J; Di Leva, F; Zizza, P; Gioiello, A; Pagano, B; Graziani, G; Tarsounas, M; Randazzo, A; Novellino, E; Biroccio, A; Cosconati, S
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/183286
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