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

TY - JOUR

T1 - Discovery of a CNS active GSK3 degrader using orthogonally reactive linker screening

AU - Holmqvist, Andreas

AU - Kocaturk, Nur Mehpare

AU - Duncan, Christina

AU - Riley, Jennifer

AU - Baginski, Steven

AU - Marsh, Graham

AU - Cresser-Brown, Joel

AU - Maple, Hannah

AU - Juvonen, Kristiina

AU - Sathe, Gajanan

AU - Morrice, Nicola

AU - Sutherland, Calum

AU - Read, Kevin D.

AU - Farnaby, William

PY - 2025/10/6

Y1 - 2025/10/6

N2 - 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.

AB - 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.

KW - Targeted Protein Degradation

KW - Direct-to-Biology

KW - Glycogen Synthase Kinase 3

KW - Central Nervous System

U2 - 10.1038/S41467-025-63928-8

DO - 10.1038/S41467-025-63928-8

M3 - Article

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

M1 - 8857

ER -