PROTACs suppression of GSK-3β, a crucial kinase in neurodegenerative diseases

• Published in: European journal of medicinal chemistry 2021-01, Vol.210, p.112949-112949, Article 112949
• Main Authors: Jiang, Xueyang, Zhou, Junting, Wang, Yang, Liu, Xin, Xu, Kaiying, Xu, Jian, Feng, Feng, Sun, Haopeng
• Format: Article
• Language: English
• Subjects: Animals; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Glycogen Synthase Kinase 3 beta - antagonists & inhibitors; Glycogen Synthase Kinase 3 beta - metabolism; Glycogen synthase kinase 3β; HT29 Cells; Humans; Models, Molecular; Neurodegenerative diseases; Neurodegenerative Diseases - drug therapy; Neurodegenerative Diseases - metabolism; PC12 Cells; Proteolysis - drug effects; Proteolysis targeting chimera; Rats; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112949

Glycogen synthase kinase 3β (GSK-3β) is involved in a variety of diseases such as neurodegenerative diseases, bipolar disorder, and diabetes. In this study, a series of heterobifunctional small molecule proteolysis targeting chimera (PROTAC) were designed and synthesized based on E3 ubiquitin ligase cereblon (CRBN). Most of PROTACs displayed good inhibitory activity, with the IC50 values at the double-digits nanomolar levels and moderate protein degradation ability against GSK-3β. Western-blot data showed compound PG21 can effectively degrade GSK-3β in a dose-dependent manner, which can induce 44.2% protein degradation at 2.8 μM. Further pharmacological experiments revealed that the ability of PG21 to degrade GSK-3β is mediated by the ubiquitin-proteasome system (UPS). In addition, PG21 protects against glutamate-induced cell death in HT-22 cells. As the first PROTAC example to degrade GSK-3β protein, the present study has provided potential candidates for further investigation in the biological function of GSK-3β protein and its association with diseases. [Display omitted] •A series of thiazolopyridyl-based PROTACs have been synthesized as GSK-3β degrader.•A powerful small molecule GSK-3β degrader PG21 was achieved.•The most promising PROTAC PG21 have high kinase selectivity profiles for the CMGC kinase family.•This is the first report of PROTAC acting on GSK-3β protein.