{"id":13425,"date":"2024-02-11T16:13:00","date_gmt":"2024-02-11T16:13:00","guid":{"rendered":"https:\/\/www.sygnaturediscovery.com\/?post_type=journal-paper&p=13425"},"modified":"2026-01-29T16:18:24","modified_gmt":"2026-01-29T16:18:24","slug":"structure-activity-relationships-for-the-g-quadruplex-targeting-experimental-drug-qn-302-and-two-analogues-probed-with-comparative-transcriptome-profiling-and-molecular-modeling","status":"publish","type":"journal-paper","link":"https:\/\/www.sygnaturediscovery.com\/fr\/journal-paper\/structure-activity-relationships-for-the-g-quadruplex-targeting-experimental-drug-qn-302-and-two-analogues-probed-with-comparative-transcriptome-profiling-and-molecular-modeling\/","title":{"rendered":"Structure\u2013activity relationships for the G-quadruplex-targeting experimental drug QN-302 and two analogues probed with comparative transcriptome profiling and molecular modeling"},"content":{"rendered":"\n

Ahmed Abdullah Ahmed,\u00a0Shuang Chen,\u00a0Maria Roman-Escorza,\u00a0Richard Angell,\u00a0Sally Oxenford,\u00a0Matthew McConville<\/strong>,\u00a0Naomi Barton,\u00a0Mihiro Sunose<\/strong>,\u00a0Dan Neidle,\u00a0Shozeb Haider,\u00a0Tariq Arshad\u00a0&\u00a0Stephen Neidle\u00a0<\/p>\n\n\n\n

Abstract<\/strong><\/p>\n\n\n\n

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\u2013activity 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.<\/p>\n\n\n\n

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