PXD065724

PXD065724 is an original dataset announced via ProteomeXchange.

Title	Discovery of a CNS active GSK3 degrader using orthogonally reactive linker screening
Description	Bifunctional targeted protein degraders, also known as Proteolysis Targeting Chimeras (PROTACs), are an emerging drug modality that may offer a new approach to understand and treat neurodegenerative diseases. These molecules have a non-occupancy based, sub-stoichiometric mechanism of action which results in removal of target proteins from cells, presenting new opportunities to interrogate and intervene in pathogenic signalling. Identifying chemical starting points for PROTACs remains a largely empirical process and the design rules for identifying in vivo quality tools to interrogate new therapeutic hypotheses in the Central Nervous System (CNS) have yet to be established. We demonstrate a concept of using orthogonally reactive linker reagents, that allowed us to construct screening libraries varying the E3 ligase recruiting ligand, the target protein recruiting ligand and the linker simultaneously and test compounds directly in cells. This led us identify a molecule directly from our screen that upon further profiling demonstrated rapid and selective Glycogen Synthase Kinase 3 (GSK3) degradation in cells, as well as CNS in vivo activity in mouse. Our findings provide new opportunities to investigate the role of GSK3 paralogs in cellular and in vivo disease models and demonstrate a successful Direct-to-Biology approach, with broad potential for identifying in vivo quality bifunctional chemical probes for CNS disease concepts.
HostingRepository	PRIDE
AnnounceDate	2025-10-13
AnnouncementXML	Submission_2025-10-12_16:25:40.969.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Gajanan Sathe
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	phosphorylated residue
Instrument	Orbitrap Ascend

Revision	Datetime	Status	ChangeLog Entry
0	2025-07-03 03:14:29	ID requested
⏵ 1	2025-10-12 16:25:41	announced

Holmqvist A, Kocaturk NM, Duncan C, Riley J, Baginski S, Marsh G, Cresser-Brown J, Maple H, Juvonen K, Sathe G, Morrice N, Sutherland C, Read KD, Farnaby W, Discovery of a CNS active GSK3 degrader using orthogonally reactive linker screening. Nat Commun, 16(1):8857(2025) [pubmed]

10.1038/s41467-025-63928-8;

submitter keyword: Targeted Protein Degradation, Central Nervous System, Glycogen Synthase Kinase 3, Direct-to-Biology

William Farnaby
contact affiliation	Principal Investigator Centre for Targeted Protein Degradation, School of Life Sciences
contact email	w.farnaby@dundee.ac.uk
lab head
Gajanan Sathe
contact affiliation	Centre for Targeted Protein Degradation (CeTPD) University of Dundee
contact email	gsathe001@dundee.ac.uk
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/2025/10/PXD065724

PRIDE project URI

• PRIDE
  1. PXD065724
     1. Label: PRIDE project
     2. Name: Discovery of a CNS active GSK3 degrader using orthogonally reactive linker screening