Tideglusib is an Irreversible GSK-3 Inhibitor

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase. Specifically, the enzyme is a key regulator of many signaling pathways. It includes cellular responses to Wnt, receptor tyrosine kinase, and G protein coupled receptor. Besides, it is involved in a wide range of cellular processes, from glycogen metabolism to cell cycle regulation and proliferation. Moreover, GSK-3 also acts as a downstream regulating switch, which determines the output of many signal pathways activated by different stimuli. The pathway of GSK-3 as a key regulator is related to the development of diseases such as diabetes, Alzheimer’s disease, bipolar disorder, and cancer.

Furthermore, GSK-3 has two mammalian isoforms encoded by different genes: GSK-3α and GSK-3β. Meanwhile, Gsk-3α and GSK-3β are active in non-stimulated cells. GSK-3 has many direct and indirect effects on cell proliferation. Nonetheless, GSK-3 can regulate the activity of transcription factors. GSK-3beta can regulate the activity of tumor suppressor TP53. Particularly, GSK-3β can phosphorylate NF-kB at s468, thereby promoting its proteasome degradation. GSK-3β can regulate the anti-apoptotic signal of BCL2L12A. BCL2L12A is a member of the anti-apoptotic Bcl-2 family. Importantly, GSK-3 is a key target for a large number of cellular processes and diseases. Now, we will introduce an irreversible GSK-3 inhibitor, Tideglusib.

Tideglusib is an Irreversible GSK-3 Inhibitor.

At first, Tideglusib (NP031112) has IC50s of 5 nM and 60 nM for GSK-3βWT and GSK-3βC199A, respectively. Incubation of both astrocyte and microglial cultures with Tideglusib completely abrogates the induction of TNF-α and COX-2 expression after glutamate treatment. Obviously, Tideglusib inhibits glutamate-induced glial activation and protects cortical neurons from cell death in vitro.

Secondly, NP031112 causes a significant reduction in the number of Annexin-V-positive cells compared with untreated neuronal cultures. Interestingly, NP031112 can be acting through a PPARγ-dependent mechanism.

Taken together, Injection of Tideglusib with 50 mg/kg into the rat hippocampus dramatically reduces kainic acid-induced inflammation. In fact, Tideglusib has a neuroprotective effect in the damaged areas of the hippocampus.

All in all, Tideglusib (NP031112) is an irreversible GSK-3 inhibitor.


Luna-Medina R, et al. J Neurosci, 2007, 27(21), 5766-5776.