PXD065822

PXD065822 is an original dataset announced via ProteomeXchange.

Title	Development of a novel therapy for systolic heart failure
Description	Heart failure presents a critical health challenge with a 5-year mortality rate of up to 50. Conventional treatments often lead to bradycardia or hypotension due to their impact on patient hemodynamics. To address this issue, we utilized high-throughput drug screening combined with structure-activity relationship-based medicinal chemistry to develop a novel drug-like compound that effectively blocks the β-adrenergic receptor (β-AR) mediated apoptosis pathway. This compound demonstrated both safety and efficacy in pre-clinical mouse models without adversely affecting cardiac output. Through thermal proteome profiling mass spectrometry, we identified the compound’s target as Wdr3, a regulator of the Hippo signaling pathway. This target identification was further validated using CRISPR-based knockout experiments. Our findings provide a valuable framework for the development of hemodynamically neutral therapies aimed at treating systolic heart failure.
HostingRepository	PRIDE
AnnounceDate	2025-09-15
AnnouncementXML	Submission_2025-09-14_17:07:06.102.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Rohan Lowe
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; acetylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2025-07-06 21:48:35	ID requested
⏵ 1	2025-09-14 17:07:06	announced

10.1038/s44321-025-00284-6;

Pollock C, Wang X, Alsaraji H, Menassa J, Mbogo G, Angage D, Richards B, Glab J, Datta KK, Theodoridis L, Petrovski S, Donner D, Lizarme-Salas Y, Du XJ, Foley M, Smith BJ, Abbott B, Puthalakath H, Development of a novel therapy for systolic heart failure. EMBO Mol Med, 17(9):2332-2353(2025) [pubmed]

submitter keyword: Apoptosis/Bim/beta-AR/HF/PKA

Hamsa Puthalakath
contact affiliation	Department of Biochemistry and Chemistry, LIMS, La Trobe University, Kingsbury Drive, Bundoora, Vic 3086, Australia
contact email	h.puthalakath@latrobe.edu.au
lab head
Rohan Lowe
contact affiliation	La Trobe University
contact email	r.lowe@latrobe.edu.au
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/2025/09/PXD065822

PRIDE project URI

• PRIDE
  1. PXD065822
     1. Label: PRIDE project
     2. Name: Development of a novel therapy for systolic heart failure