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Structure–activity relationships for the G-quadruplex-targeting experimental drug QN-302 and two analogues probed with comparative transcriptome profiling and molecular modeling

Ahmed, Ahmed Abdullah, Chen, Shuang, Roman-Escorza, Maria, Angell, Richard, Oxenford, Sally, McConville, Matthew, Barton, Naomi, Sunose, Mihiro, Neidle, Dan, Haider, Shozeb, Arshad, Tariq and Neidle, Stephen 2024. Structure–activity relationships for the G-quadruplex-targeting experimental drug QN-302 and two analogues probed with comparative transcriptome profiling and molecular modeling. Scientific Reports 14 (1) , 3447. 10.1038/s41598-024-54080-2

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Schools > Biosciences
Additional Information: License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher: Nature Research
ISSN: 2045-2322
Date of First Compliant Deposit: 12 February 2024
Date of Acceptance: 8 February 2024
Last Modified: 12 Feb 2024 11:45
URI: https://orca.cardiff.ac.uk/id/eprint/166258

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