2. Academic Validation
  3. Discovery of a CNS active GSK3 degrader using orthogonally reactive linker screening

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

  • Nat Commun. 2025 Oct 6;16(1):8857. doi: 10.1038/s41467-025-63928-8.
Andreas Holmqvist # 1,  Nur Mehpare Kocaturk # 1,  Christina Duncan 2,  Jennifer Riley 2,  Steven Baginski 2,  Graham Marsh 3,  Joel Cresser-Brown 3,  Hannah Maple 3,  Kristiina Juvonen 1,  Gajanan Sathe 1,  Nicola Morrice 4,  Calum Sutherland 5,  Kevin D Read 2,  William Farnaby 6
Affiliations

Affiliations

  • 1 Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, Dundee, UK.
  • 2 Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, UK.
  • 3 Bio-Techne (Tocris), The Watkins Building, Atlantic Road, Avonmouth, Bristol, UK.
  • 4 Division of Neuroscience, School of Medicine, IMS/WTB Complex, University of Dundee, Dundee, UK.
  • 5 School of Medicine, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK.
  • 6 Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, Dundee, UK. [email protected].
  • # Contributed equally.
PMID: 41053170 DOI: 10.1038/s41467-025-63928-8
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.

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