GSK-3 inhibitors have emerged as promising tools in biomedical research, offering profound insights into the complex signaling networks regulated by glycogen synthase kinase (GSK)-3 and holding potential for therapeutic development across a spectrum of diseases, including neurodegenerative disorders, cancer, and type 2 diabetes. Glycogen synthase kinase-3, a serine/threonine kinase, exists in two major isoforms (GSK-3α and GSK-3β) that share high sequence homology but exhibit distinct tissue distribution and functional specificities, with GSK-3β being the more extensively studied isoform in pathological processes. As key regulators of numerous cellular pathways, GSK-3 enzymes modulate processes such as glycogen metabolism, cell cycle progression, apoptosis, and gene transcription by phosphorylating a diverse array of substrates. The development and application of GSK-3 inhibitors have thus become central to deciphering the intricate mechanisms underlying GSK-3-mediated signaling and exploring its therapeutic relevance.
GSK-3 inhibiteurs (GSK-3 Inhibitors)
| N° de cat. | Nom du produit | Informations | Citations dutilisation du produit | Validations de produit |
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| S1263 | CHIR-99021 (Laduviglusib) | Laduviglusib (CHIR-99021, CT99021) est un inhibiteur de GSK-3α et GSK-3β avec des valeurs d'IC50 de 10 nM et 6,7 nM, respectivement. Il ne présente pas de réactivité croisée contre les kinases cycline-dépendantes (CDK) et montre une sélectivité 350 fois supérieure pour la GSK-3β par rapport aux CDK. Ce composé fonctionne comme un activateur de Wnt/β-caténine et induit l'autophagie. |
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| S2924 | Laduviglusib (CHIR-99021) Hydrochloride | Laduviglusib (CHIR-99021; CT99021) HCl est le chlorhydrate de CHIR-99021, un inhibiteur de la GSK-3 l/ l avec un IC50 de 10 nM/6,7 nM; CHIR-99021 montre une s llectivit l sup lrieure l 500 fois pour la GSK-3 par rapport l ses homologues les plus proches Cdc2 et ERK2. CHIR-99021 est un puissant activateur pharmacologique de la voie de signalisation Wnt/b lta-cat lenine. CHIR-99021 r lscue significativement l'autophagie induite par la lumi lre et augmente les prot leines GR, ROR l et li les l l'autophagie. |
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| S1075 | SB216763 | Le SB216763 est un inhibiteur puissant et sélectif de la GSK-3 avec une IC50 de 34,3 nM pour la GSK-3α et est tout aussi efficace pour inhiber la GSK-3β humaine. Ce composé active l'autophagy. |
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| S2745 | CHIR-98014 | CHIR-98014 (CT98014) est un puissant inhibiteur de la GSK-3α/β avec une IC50 de 0,65 nM/0,58 nM dans des essais sans cellules, avec la capacité de distinguer la GSK-3 de ses homologues les plus proches Cdc2 et ERK2. |
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| S1590 | TWS119 | TWS119 est un inhibiteur de la GSK-3β avec une IC50 de 30 nM dans un essai sans cellules; ce composé est capable d'induire la différenciation neuronale et peut être utile pour la biologie des cellules souches. L'inhibition de la GSK-3β par ce produit chimique déclenche l'autophagy. |
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| S7198 | GSK-3 Inhibitor IX (BIO) | Le BIO (GSK-3 Inhibitor IX, 6-bromoindirubin-3-oxime, 6-Bromoindirubin-3'-oxime, MLS 2052) est un inhibiteur spécifique de GSK-3 avec un IC50 de 5 nM pour GSK-3α/β dans un essai sans cellules, montre une sélectivité >16 fois supérieure à celle de CDK5, et est également un inhibiteur pan-JAK avec un IC50 de 30 nM pour Tyk2. Le BIO induit l'apoptose dans les cellules de mélanome humain. |
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| S7063 | LY2090314 | LY2090314 est un puissant inhibiteur de GSK-3 pour GSK-3 R R/ R R avec une IC50 de 1,5 nM/0,9 nM; il peut améliorer l'efficacité des régimes de chimiothérapie à base de platine. Ce composé est hautement sélectif envers GSK3, comme démontré par sa sélectivité relative à un large panel de kinases. |
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| S2823 | Tideglusib | Tideglusib est un inhibiteur irréversible, non ATP-compétitif de GSK-3β avec une IC50 de 60 nM dans un test sans cellules ; ce composé n'inhibe pas les kinases avec une Cys homologue à la Cys-199 située dans le site actif. Phase 2. |
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| S2729 | SB415286 | SB415286 est un puissant inhibiteur de GSK3α avec un IC50/Ki de 78 nM/31 nM, et une inhibition tout aussi efficace de GSK-3β. Ce composé provoque l'arrêt de la croissance et l'apoptose des cellules de MM. |
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| S7435 | AR-A014418 | AR-A014418 (GSK-3β Inhibitor VIII) est un inhibiteur sélectif de GSK3β, compétitif de l'ATP, avec un IC50 et un Ki de 104 nM et 38 nM dans des essais sans cellules, sans inhibition significative sur 26 autres kinases testées. |
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Glycogen Synthase Kinase-3: Structure and Isoform-Specific Functions
Glycogen synthase kinase-3 (GSK-3) is a constitutively active kinase that was initially identified for its role in regulating glycogen synthesis by phosphorylating and inactivating glycogen synthase. Subsequent research has revealed that GSK-3 exists as two isoforms, GSK-3α (51 kDa) and GSK-3β (47 kDa), which are encoded by separate genes (GSK3A and GSK3B, respectively) and share approximately 97% homology in their catalytic domains but differ in their N- and C-terminal regions. These structural differences contribute to isoform-specific interactions with regulatory proteins and substrates, leading to distinct functional outcomes. GSK-3β, in particular, has been implicated in a wide range of disease-related pathways, making it a primary target for inhibitor development in research investigations.
Structural Basis of GSK-3 Kinase Activity
The catalytic domain of GSK-3 contains the conserved kinase fold, consisting of an N-terminal lobe rich in β-sheets and a C-terminal lobe dominated by α-helices, with the active site located at the interface between the two lobes. A unique feature of GSK-3 is its requirement for a "priming phosphate" on substrates, which binds to an arginine-rich pocket (the "priming site") adjacent to the active site, enabling efficient phosphorylation of the substrate at a serine or threonine residue four positions C-terminal to the priming phosphate. This priming-dependent mechanism distinguishes GSK-3 from many other kinases and dictates its substrate specificity. The constitutive activity of GSK-3 is attributed to the absence of an autoinhibitory domain, with regulation primarily occurring through post-translational modifications (e.g., phosphorylation, ubiquitination) and interactions with regulatory proteins.
Isoform-Specific Roles of GSK-3α and GSK-3β
While GSK-3α and GSK-3β share overlapping substrates and functions, accumulating evidence indicates isoform-specific roles in cellular processes and disease pathogenesis. GSK-3α is predominantly expressed in adipose tissue, liver, and brain, and has been linked to glycogen metabolism and insulin resistance. In contrast, GSK-3β is ubiquitously expressed and plays critical roles in inflammation, cell survival, and neurodegeneration. For example, in Alzheimer’s disease (AD), GSK-3β phosphorylates the microtubule-associated protein tau, leading to the formation of neurofibrillary tangles, a hallmark of AD pathology. In cancer, GSK-3β exhibits both tumor-promoting and tumor-suppressive roles depending on the cellular context, regulating the activity of oncogenes such as β-catenin and p53. These isoform-specific functions highlight the importance of developing selective GSK-3 inhibitors in research to dissect the distinct roles of GSK-3α and GSK-3β.
Pathway Modulation by GSK-3 Inhibitors: Key Signaling Networks
GSK-3 is a central node in numerous signaling pathways, integrating inputs from upstream regulators such as the PI3K/Akt, Wnt, and MAPK pathways. GSK-3 inhibitors exert their effects by disrupting these pathways, leading to downstream changes in gene expression and cellular function. Understanding the pathway-specific effects of GSK-3 inhibitors is critical for their application in research and therapeutic development, as it enables the identification of context-dependent outcomes and potential off-target effects.
Wnt/β-Catenin Pathway Regulation by GSK-3β Inhibitors
The Wnt/β-catenin pathway is one of the most well-characterized pathways regulated by GSK-3β. In the absence of Wnt signaling, GSK-3β forms a destruction complex with adenomatous polyposis coli (APC), axin, and casein kinase 1 (CK1), which phosphorylates β-catenin, targeting it for ubiquitination and proteasomal degradation. GSK-3β inhibitors disrupt this destruction complex, preventing β-catenin phosphorylation and leading to its accumulation in the cytoplasm and nucleus. Nuclear β-catenin then binds to T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors, activating the expression of target genes involved in cell proliferation and differentiation. This pathway modulation is particularly relevant in stem cell research, where GSK-3 inhibitors are used to maintain pluripotency, and in cancer research, where aberrant Wnt/β-catenin signaling drives tumorigenesis.
PI3K/Akt Pathway and GSK-3 Kinase Inhibition
The PI3K/Akt pathway is a major upstream regulator of GSK-3, with Akt phosphorylating GSK-3α at Ser21 and GSK-3β at Ser9, leading to their inactivation. GSK-3 inhibitors mimic this inhibitory effect, bypassing upstream signaling events to directly block GSK-3 activity. This pathway modulation has significant implications in neurodegenerative disease research, as the PI3K/Akt/GSK-3 axis is dysregulated in AD, Parkinson’s disease, and Huntington’s disease. In preclinical studies, GSK-3 inhibitors have been shown to reduce tau phosphorylation, protect against neuronal apoptosis, and improve cognitive function in animal models of AD. Additionally, in metabolic research, GSK-3 inhibitors enhance insulin sensitivity by regulating glycogen synthesis and glucose uptake, making them potential candidates for the treatment of type 2 diabetes.
Substrates of GSK-3: Specificity and Regulatory Mechanisms in Inhibition
GSK-3 phosphorylates over 100 substrates, including transcription factors, cytoskeletal proteins, metabolic enzymes, and signaling molecules, highlighting its pleiotropic roles in cellular physiology. The specificity of GSK-3 inhibitors for substrate phosphorylation is a critical consideration in research, as off-target effects on non-GSK-3 substrates or isoform-specific substrates can complicate data interpretation. Understanding the regulatory mechanisms that govern GSK-3-substrate interactions is essential for the development of selective inhibitors and the accurate interpretation of their biological effects.
Substrate Specificity of GSK-3β: Priming-Dependent and Priming-Independent Mechanisms
As mentioned earlier, most GSK-3 substrates require a priming phosphate for efficient phosphorylation, a mechanism that contributes to substrate specificity. For example, glycogen synthase is primed by casein kinase 2, while β-catenin is primed by CK1. However, some substrates, such as p53 and heat shock protein 90 (Hsp90), are phosphorylated by GSK-3β in a priming-independent manner, expanding the range of cellular processes regulated by this kinase. GSK-3 inhibitors can block both priming-dependent and priming-independent phosphorylation, but the extent of inhibition varies depending on the inhibitor’s binding mode and specificity for GSK-3 isoforms. In research, this substrate specificity is exploited to dissect the role of individual GSK-3 substrates in disease pathways, for example, by using inhibitors to selectively block the phosphorylation of tau in neurodegeneration research.
Regulation of GSK-3 Substrate Phosphorylation by Inhibitors
The regulation of GSK-3 substrate phosphorylation by inhibitors is a complex process that involves not only direct inhibition of kinase activity but also indirect effects on upstream signaling pathways and regulatory proteins. For instance, some GSK-3 inhibitors bind to the active site of the kinase, competing with ATP and preventing substrate phosphorylation. Others bind to allosteric sites, inducing conformational changes that reduce kinase activity. Additionally, GSK-3 inhibitors can modulate the expression of regulatory proteins that interact with GSK-3, such as axin and APC, further influencing substrate phosphorylation. In research, techniques such as mass spectrometry and phospho-specific antibodies are used to characterize the substrate-specific effects of GSK-3 inhibitors, enabling the identification of novel downstream targets and the validation of inhibitor specificity.
GSK-3 Inhibitors in Scientific Research: Tools and Translational Potential
GSK-3 inhibitors have become indispensable tools in scientific research, facilitating the dissection of GSK-3-mediated pathways and the validation of GSK-3 as a therapeutic target. A wide range of GSK-3 inhibitors have been developed, including synthetic small molecules (e.g., SB216763, CHIR99021), natural products (e.g., lithium, curcumin), and peptide inhibitors. These inhibitors vary in their potency, selectivity for GSK-3 isoforms, and binding modes, making them suitable for different research applications. For example, CHIR99021, a selective GSK-3β inhibitor, is commonly used in stem cell research to maintain pluripotency, while SB216763 is used to study the role of GSK-3 in neurodegeneration.
Despite their utility in research, the translational potential of GSK-3 inhibitors has been hindered by challenges such as off-target effects, toxicity, and limited efficacy in clinical trials. However, recent advances in structure-based drug design have led to the development of more selective and potent GSK-3 inhibitors, addressing some of these limitations. For example, inhibitors that target the unique N-terminal region of GSK-3β have been shown to exhibit higher isoform specificity, reducing off-target effects on GSK-3α. Additionally, combination therapies involving GSK-3 inhibitors and other pathway modulators are being explored in cancer and neurodegenerative disease research, aiming to enhance efficacy and reduce toxicity.
In conclusion, GSK-3 inhibitors have significantly advanced our understanding of glycogen synthase kinase-3-mediated pathways, substrate regulation, and isoform-specific functions. As research continues to unravel the complex mechanisms underlying GSK-3 activity and the effects of inhibition, the development of more selective and effective GSK-3 inhibitors holds great promise for the treatment of a wide range of diseases. The ongoing integration of structural biology, proteomics, and preclinical models in GSK-3 inhibitor research will continue to drive scientific progress and translational success in this field.
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