eprintid: 10205711
rev_number: 7
eprint_status: archive
userid: 699
dir: disk0/10/20/57/11
datestamp: 2025-03-07 11:41:49
lastmod: 2025-03-07 11:41:49
status_changed: 2025-03-07 11:41:49
type: article
metadata_visibility: show
sword_depositor: 699
creators_name: Tosoni, Beatrice
creators_name: Naghshineh, Eisa
creators_name: Zanin, Irene
creators_name: Gallina, Irene
creators_name: Di Pietro, Lorenzo
creators_name: Cleris, Loredana
creators_name: Nadai, Matteo
creators_name: Lecchi, Mara
creators_name: Verderio, Paolo
creators_name: Pratesi, Pietro
creators_name: Pasquali, Sandro
creators_name: Zaffaroni, Nadia
creators_name: Neidle, Stephen
creators_name: Folini, Marco
creators_name: Richter, Sara N
title: The G-quadruplex experimental drug QN-302 impairs liposarcoma cell growth by inhibiting MDM2 expression and restoring p53 levels
ispublished: pub
divisions: UCL
divisions: B02
divisions: C08
divisions: D10
note: 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.
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.
date: 2025-02-28
date_type: published
publisher: OXFORD UNIV PRESS
official_url: https://doi.org/10.1093/nar/gkaf085
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 2361726
doi: 10.1093/nar/gkaf085
medium: Print
pii: 8010959
lyricists_name: Neidle, Stephen
lyricists_id: SNEID18
actors_name: Harris, Jean
actors_id: JAHAR68
actors_role: owner
funding_acknowledgements: 2025 [AIRC]
full_text_status: public
publication: Nucleic Acids Research
volume: 53
number: 4
article_number: gkaf085
pages: 17
event_location: England
issn: 0305-1048
citation:        Tosoni, Beatrice;    Naghshineh, Eisa;    Zanin, Irene;    Gallina, Irene;    Di Pietro, Lorenzo;    Cleris, Loredana;    Nadai, Matteo;                                 ... Richter, Sara N; + view all <#>        Tosoni, Beatrice;  Naghshineh, Eisa;  Zanin, Irene;  Gallina, Irene;  Di Pietro, Lorenzo;  Cleris, Loredana;  Nadai, Matteo;  Lecchi, Mara;  Verderio, Paolo;  Pratesi, Pietro;  Pasquali, Sandro;  Zaffaroni, Nadia;  Neidle, Stephen;  Folini, Marco;  Richter, Sara N;   - view fewer <#>    (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 <https://doi.org/10.1093/nar%2Fgkaf085>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10205711/1/The%20G-quadruplex%20experimental%20drug%20QN-302%20impairs%20liposarcoma%20cell%20growth%20by%20inhibiting%20MDM2%20expression%20and%20restoring%20p53%20le.pdf