title: Exploring the chemical space of G-quadruplex binders: discovery of a novel chemotype targeting the human telomeric sequence.
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.
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego 30, 16163 Genova, Italy.
authors.forename: Francesco Saverio
authors.initials: FS
authors.lastname: Di Leva
authors.forename: Pasquale
authors.initials: P
authors.lastname: Zizza
authors.forename: Chiara
authors.initials: C
authors.lastname: Cingolani
authors.forename: Carmen
authors.initials: C
authors.lastname: D'Angelo
authors.forename: Bruno
authors.initials: B
authors.lastname: Pagano
authors.forename: Jussara
authors.initials: J
authors.lastname: Amato
authors.forename: Erica
authors.initials: E
authors.lastname: Salvati
authors.forename: Claudia
authors.initials: C
authors.lastname: Sissi
authors.forename: Odra
authors.initials: O
authors.lastname: Pinato
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Antonio
authors.initials: A
authors.lastname: Randazzo
authors.forename: Annamaria
authors.initials: A
authors.lastname: Biroccio
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D031541:Fluorescence Resonance Energy Transfer; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D016615:Telomere / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands