Discovery of a CNS active GSK3 degrader using orthogonally reactive linker screening

Andreas Holmqvist, Nur Mehpare Kocaturk, Christina Duncan, Jennifer Riley, Steven Baginski, Graham Marsh, Joel Cresser-Brown, Hannah Maple, Kristiina Juvonen, Gajanan Sathe, Nicola Morrice, Calum Sutherland, Kevin D. Read and William Farnaby ()
Additional contact information
Andreas Holmqvist: University of Dundee
Nur Mehpare Kocaturk: University of Dundee
Christina Duncan: University of Dundee
Jennifer Riley: University of Dundee
Steven Baginski: University of Dundee
Graham Marsh: Avonmouth
Joel Cresser-Brown: Avonmouth
Hannah Maple: Avonmouth
Kristiina Juvonen: University of Dundee
Gajanan Sathe: University of Dundee
Nicola Morrice: University of Dundee
Calum Sutherland: University of Dundee
Kevin D. Read: University of Dundee
William Farnaby: University of Dundee

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Bifunctional targeted protein degraders, also known as Proteolysis Targeting Chimeras (PROTACs), are an emerging drug modality that may offer a new approach for treating neurodegenerative diseases. Identifying chemical starting points for PROTACs remains a largely empirical process and the design rules for identifying Central Nervous System (CNS) active PROTACs have yet to be established. Here we demonstrate a concept of using orthogonally reactive linker reagents, that allow the construction of screening libraries whereby the E3 ligase binder, the target protein binder and the linker can be simultaneously varied and tested directly in cellular assays. This approach enabled the discovery of Glycogen Synthase Kinase 3 (GSK3) PROTACs which are CNS in vivo active in female mice. Our findings provide opportunities to investigate the role of GSK3 paralogs in cellular and in vivo disease models and for the rapid discovery of in vivo quality bifunctional chemical probes for CNS disease concepts.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-63928-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63928-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-63928-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().