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

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.

G-四链体（G-quadruplex）稳定剂是抗癌化疗领域一类已被证实的研究靶点。为规避G4配体的抗增殖作用，癌细胞会在端粒处招募PARP（多聚ADP核糖聚合酶）。本研究中，我们基于本团队此前发现的强效G4配体与一款同家族PARP抑制剂的结构相似性，合成了衍生物库以开发首款双靶点G4/PARP配体。我们证实，一款经合理修饰的噻吩并[3,2-c]喹啉-4(5H)-酮可在体外及细胞层面稳定G4折叠结构，诱导定位于端粒的DNA损伤应答，抑制细胞内的多聚ADP核糖基化修饰，并对BRCA2缺陷型肿瘤细胞展现出抗增殖活性。