PXD059756

PXD059756 is an original dataset announced via ProteomeXchange.

Title	Selectivity for TP53 signalling drives the mode of action of a highly potent N,O,O-tridentate naphthoquinone-based organoruthenium anticancer drug candidate – in vitro
Description	The candidate metallodrug [(3-ethyl-4-oxo-(pyrazolyl)-dihydronaphthalene)(cymene)ruthenium(II)] (1a) was recently shown to exhibit exceptional nanomolar activity in the chemo-resistant SW480 cancer cell line. This study was performed to elucidate the determining parameters of the mode of action of this N,O,O-tridentate organoruthenium compound in vitro and in vivo. For this purpose, four metal(arenes) based on 3-ethyl naphthoquinone (3Et-NQ, a) and 3-morpholine naphthoquinone (3Morph-NQ, b) with ruthenium (1) and osmium (2) were synthesized and characterized. The four compounds were stable in aqueous solution and exhibited ligand- and metal-dependent reactivity towards biological nucleophiles with a selectivity for amino acids over nucleotides at biologically relevant concentrations. Drug effects were elucidated by proteome profiling at subcellular resolution, i.e. by assessing cytoplasmic and nuclear fractions of SW480 cells separately. The ruthenium- and osmium(arene) derivatives containing the 3Et-NQ ligand revealed down-regulated TP53 as a central hub in the perturbation network, connected to down-regulated proliferative MAPK3 signalling. Complex 1a was most active in the SW480 cell line suggesting selectivity for mutant TP53. The 3Et-NQ complexes, particularly 1a, led to tumour inhibition in a CT26 colon carcinoma mouse model, while the 3Morph-NQ complexes were inactive. Tissue proteomic analysis of livers of 1a-treated mice displayed similar stress responses as observed in vitro. Finally, tumour tissues revealed a pronounced down-regulation of Egfr, which is linked to TP53 signalling and confirmed its MoA in vivo.
HostingRepository	PRIDE
AnnounceDate	2025-08-25
AnnouncementXML	Submission_2025-08-25_05:27:37.201.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Christopher Gerner
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2025-01-13 22:51:35	ID requested
⏵ 1	2025-08-25 05:27:38	announced

Rosner A, Skos L, Mendrina T, Baier D, Hejl M, Borutzki Y, Gradl M, Geisler H, Mohr T, Legin A, Jakupec MA, Bileck A, Gerner C, Koellensperger G, Heffeter P, Berger W, Keppler BK, Kandioller W, Meier-Menches SM, -tridentate naphthoquinone-based organo-ruthenium anticancer drug candidate. Chem Sci, 16(34):15652-15665(2025) [pubmed]

10.1039/d5sc00735f;

submitter keyword: Cancer

In vivo

Metal(arene)

Metals in medicine

Mode of Action

Ruthenium

Osmium

Structure-activity relationship

Christopher Gerner
contact affiliation	University of Vienna, Faculty of Chemistry, Department of Analytical Chemistry
contact email	christopher.gerner@univie.ac.at
lab head
Christopher Gerner
contact affiliation	University of Vienna
contact email	christopher.gerner@univie.ac.at
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/08/PXD059756

PRIDE project URI

• PRIDE
  1. PXD059756
     1. Label: PRIDE project
     2. Name: Selectivity for TP53 signalling drives the mode of action of a highly potent N,O,O-tridentate naphthoquinone-based organoruthenium anticancer drug candidate – in vitro