Structure–activity relationships for the G-quadruplex-targeting experimental drug QN-302 and two analogues probed with comparative transcriptome profiling and molecular modeling
Ahmed A. Ahmed, Shuang Chen, Maria Roman-Escorza, Richard Angell, Sally Oxenford, Matthew McConville, Naomi Barton, Mihiro Sunose, Dan M. Neidle, Shozeb Haider, Tariq Arshad, Stephen Neidle
Abstract
The tetrasubstituted naphthalene diimide compound QN-302 binds to G-quadruplex (G4) DNA structures. It shows high potency in pancreatic ductal adenocarcinoma (PDAC) cells and inhibits the transcription of cancer-related genes in these cells and in PDAC animal models. It is currently in Phase 1a clinical evaluation as an anticancer drug. A study of structure-activity relationships of QN-302 and two related analogues (CM03 and SOP1247) is reported here. These have been probed using comparisons of transcriptional profiles from whole-genome RNA-seq analyses, together with molecular modelling and molecular dynamics simulations. Compounds CM03 and SOP1247 differ by the presence of a methoxy substituent in the latter: these two compounds have closely similar transcriptional profiles. Whereas QN-302 (with an additional benzyl-pyrrolidine group), although also showing down-regulatory effects in the same cancer-related pathways, has effects on distinct genes, for example in the hedgehog pathway. This distinctive pattern of genes affected by QN-302 is hypothesized to contribute to its superior potency compared to CM03 and SOP1247. Its enhanced ability to stabilize G4 structures has been attributed to its benzyl-pyrrolidine substituent fitting into and filling most of the space in a G4 groove compared to the hydrogen atom in CM03 or the methoxy group substituent in SOP1247.