5-Imino-1,2,4-Thiadiazoles: First Small Molecules As Substrate Competitive Inhibitors of Glycogen Synthase Kinase 3

Abstract

Cumulative evidence strongly supports that glycogen synthase kinase-3 (GSK-3) is a pathogenic molecule when it is up-dysregulated, emerging as an important therapeutic target in severe unmet human diseases. GSK-3 specific inhibitors might be promising effective drugs for the treatment of devastating pathologies such as neurodegenerative diseases, stroke, and mood disorders. As GSK-3 has the ability to phosphorylate primed substrates, small molecules able to bind to this site should be perfect drug candidates, able to partially block the activity of the enzyme over some specific substrates. Here, we report substituted 5-imino-1,2,4-thiadiazoles as the first small molecules able to inhibit GSK-3 in a substrate competitive manner. These compounds are cell permeable, able to decrease inflammatory activation and to selectively differentiate neural stem cells. Overall, 5-imino-1,2,4-thiadiazoles are presented here as new molecules able to decrease neuronal cell death and to increase endogenous neurogenesis blocking the GSK-3 substrate site.

The Role of Wnt/β-Catenin Signaling Pathway in Disrupted Hippocampal Neurogenesis of Temporal Lobe Epilepsy: A Potential Therapeutic Target?

“…NP03112, also called tideglusib, was demonstrated by Morales-Garcia et al [101] to induce neurogenesis in the DG of adult rats. In addition, Palomo et al [102] reported substituted 5-imino-1,2,4-thiadiazoles was able to inhibit GSK-3 in a substrate competitive manner and selectively differentiate NSCs in vitro. These GSK-3 inhibitors may represent new potential therapeutic drugs and worth further investigation in epilepsy models.…”

Identification in Silico and Experimental Validation of Novel Phosphodiesterase 7 Inhibitors with Efficacy in Experimental Autoimmune Encephalomyelitis Mice

“…30 We have recently reported this class of compounds, the ITDZs, as substrate competitive inhibitors of GSK3 with potential for the treatment of neurodegenerative diseases. 21 As synergistic interactions between PDE4B and GSK3 inhibitors have been suggested due to the influence of increased cAMP levels induced by PDE4B inhibitors on GSK3 function, 43 our ITDZ compounds offer a unique potential to be explored as innovative multifunctional neurological drugs without the emetic effects present in PDE4B inhibitors. In fact, one of the member of this family (compound 7) has expressed antipsychotic capacities and ameliorated certain cognitive domains relevant to schizophrenia assessed in vivo.…”

“…As aqueous solubility of lipophilic scaffolds is often improved by the attachment of a morpholine unit, 46 we selected derivative 15 containing this unit, as candidate for further progression. Its capacity to cross the BBB 21 and its safety in the Ames test, prompted us to evaluate it in chronic experimental autoimmune encephalomyelitis (EAE) mice, a well established murine model for multiple sclerosis where GSK3β 22 and PDE7 inhibitors 11 have shown separately efficacy.…”

Identification of Novel Glycogen Synthase Kinase-3? Inhibitor through Combined Shape-Based Screening and Molecular Docking Approach

“…[10][11] Currently, this drug is being evaluated in adolescents with Autism Spectrum Disorders (ASD) to improve their social behavior. [12] All currently available molecules that specifically target the substrate binding site (L807mts peptide and 5-Imino1,2,4-Thiadiazoles) [13][14] and allosteric site (a quinoline derivative V.P.0.7) [15] provides selective and subtle modulation of kinase. However, a journey to the clinic with a series of highly selective and potent small molecule GSK-3β targeted therapy is still a challenging task.…”