Tosoni, Beatrice;
Naghshineh, Eisa;
Zanin, Irene;
Gallina, Irene;
Di Pietro, Lorenzo;
Cleris, Loredana;
Nadai, Matteo;
... Richter, Sara N; + view all
(2025)
The G-quadruplex experimental drug QN-302 impairs liposarcoma cell growth by inhibiting MDM2 expression and restoring p53 levels.
Nucleic Acids Research
, 53
(4)
, Article gkaf085. 10.1093/nar/gkaf085.
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Abstract
Well-differentiated/dedifferentiated liposarcomas (WD/DDLPSs) account for ∼60% of all liposarcomas. They have a poor prognosis due to limited therapeutic options. WD/DDLPSs are characterized by aberrant expression of mouse double minute 2 (MDM2), which forms G-quadruplexes (G4s) in its promoter. Here, we investigated the possibility of targeting WD/DDLPSs with small molecules against the MDM2 G4s. Among the molecules tested, the naphthalene diimide derivative QN-302 significantly impaired WD/DDLPS cell growth and its activity strikingly paralleled cell-specific G4 abundance as measured by CUT&Tag and RNA sequencing analysis. QN-302 stabilized MDM2 G4s at the P2 inducible promoter and prevented polymerase progression from the constitutive P1 promoter, thereby inhibiting the formation of full-length MDM2 transcripts. This resulted in the accumulation of p53 through the p53-MDM2 autoregulatory feedback loop, ultimately leading to apoptotic cell death. In patient-derived xenograft mouse models, QN-302 treatment reduced tumour volume distribution and was well tolerated. We have identified a novel and effective therapeutic strategy to reduce MDM2 expression and promote p53 reactivation in tumours harbouring wild-type TP53, such as WD/DDLPSs.
| Type: | Article |
|---|---|
| Title: | The G-quadruplex experimental drug QN-302 impairs liposarcoma cell growth by inhibiting MDM2 expression and restoring p53 levels |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/nar/gkaf085 |
| Publisher version: | https://doi.org/10.1093/nar/gkaf085 |
| Language: | English |
| Additional information: | Copyright © The Author(s) 2025. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10205711 |
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