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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.

Original publication

DOI

10.1021/acs.jmedchem.6b01563

Type

Journal article

Journal

J Med Chem

Publication Date

11/05/2017

Volume

60

Pages

3626 - 3635

Keywords

Antineoplastic Agents, Cell Line, Tumor, Drug Discovery, Drug Screening Assays, Antitumor, Fluorescence Resonance Energy Transfer, Fluorescent Antibody Technique, G-Quadruplexes, Humans, Poly(ADP-ribose) Polymerase Inhibitors