The DNA damaging properties of the experimental G-quadruplex (G4) drug QN-302 are potentiated by the DNA repair inhibitor Olaparib and mitigated by the molecular helicase PhpC

BackgroundQN-302 is a tetra-substituted naphthalene diimide (NDI) compound designed to interact with G-quadruplex (G4) DNA. QN-302 is currently being evaluated in a phase 1 clinical trial on patients with advanced pancreatic ductal adenocarcinoma (PDAC) and other solid tumors. However, the mechanistic origin(s) of its anticancer activity remains to be fully understood. ResultsWe report herein the ability of QN-302 to damage DNA at G4 sites in cancer cells. To this end, we implemented a series of in vitro assays (FQA and FRET-melting) and cell-based techniques (in situ click imaging and immunodetection) that concurred in demonstrating both the DNA damaging properties of QN-302 and its ability to engage G4s in human cancer cells. Then, we investigate its anticancer effects in PDAC (MIA PaCa-2 cells) and show that it can be efficiently potentiated upon combination with Olaparib, an inhibitor of DNA repair, in an approach referred to as chemically induced synthetic lethality. ConclusionThis study not only confirms the excellent anticancer properties of QN-302 in human cancer cells but also provides insights into its mechanism of action. The optimization of this therapeutic activity by combination with Olaparib opens a promising new avenue for improving its clinical efficacy.