TY  - JOUR
JF  - Nucleic Acids Research
A1  - Tosoni, Beatrice
A1  - Naghshineh, Eisa
A1  - Zanin, Irene
A1  - Gallina, Irene
A1  - Di Pietro, Lorenzo
A1  - Cleris, Loredana
A1  - Nadai, Matteo
A1  - Lecchi, Mara
A1  - Verderio, Paolo
A1  - Pratesi, Pietro
A1  - Pasquali, Sandro
A1  - Zaffaroni, Nadia
A1  - Neidle, Stephen
A1  - Folini, Marco
A1  - Richter, Sara N
N2  - 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.
ID  - discovery10205711
UR  - https://doi.org/10.1093/nar/gkaf085
PB  - OXFORD UNIV PRESS
SN  - 0305-1048
IS  - 4
N1  - 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.
TI  - The G-quadruplex experimental drug QN-302 impairs liposarcoma cell growth by inhibiting MDM2 expression and restoring p53 levels
AV  - public
VL  - 53
Y1  - 2025/02/28/
EP  - 17
ER  -