Tideglusib
(Synonyms: 4-苄基-2-(萘-1-基)-[1,2,4]噻二唑烷-3,5-二酮,NP031112) 目录号 : GC14465
Tideglusib是一种强效、选择性且不可逆的非ATP竞争性糖原合成酶激酶-3（GSK-3）抑制剂，对GSK-3βWT和GSK-3βC199A的IC50分别为5nM和60nM。
Cas No.:865854-05-3
Sample solution is provided at 25 µL, 10mM.
Tideglusib is a potent, selective, and irreversible non-ATP competitive glycogen synthase kinase-3 (GSK-3) inhibitor. The IC50 values for GSK-3βWT and GSK-3βC199A are 5nM and 60nM, respectively [1]. GSK-3 is a serine/threonine kinase that is associated with glucose regulation, apoptosis, protein synthesis, cell signaling, cell transport, gene transcription, and cell proliferation [2]. Tideglusib can inhibit inflammation and neurodegenerative diseases and can be used to treat Alzheimer's disease [3-4].
In vitro, Tideglusib (2.5μM; 24h) completely eliminated the expression of TNF-α and COX-2 in glutamate-induced astrocyte and microglial cell cultures, and significantly reduced the number of laminin-V positive cells, exerting anti-inflammatory and neuroprotective effects on cortical neurons [5]. Different concentrations of Tideglusib (5-120μM; 48h) dose-dependently reduced the cell viability of human neuroblastoma (IMR32) cells [6].
In vivo, Tideglusib (2ng/2.5μl PBS; stereotactic injection) treatment significantly improved brain injury in kainic acid (KA) induced focal excitotoxicity model rats and reduced TNF-α positive staining in astrocytes and microglia [5]. Tideglusib (200mg/kg/day; 3 months) oral treatment reduced tau protein phosphorylation levels in APP/tau double transgenic mice, decreased amyloid protein deposition and plaque-related astrocyte proliferation, and protected the entorhinal cortex and prevented hippocampal CA1 zone neuron death [7].
References:
[1] Domínguez JM, Fuertes A, Orozco L, et al. Evidence for irreversible inhibition of glycogen synthase kinase-3β by tideglusib. J Biol Chem. 2012;287(2):893-904.
[2] Pandey M K, DeGrado T R. Glycogen synthase kinase-3 (GSK-3)-targeted therapy and imaging[J]. Theranostics, 2016, 6(4): 571.
[3] Serenóa L, Coma M, Rodríguez M, et al. A novel GSK-3β inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo. Neurobiol Dis. 2009 Sep; 35(3): 359-67.
[4] Lovestone S, Boada M, Dubois B, et al. A phase II trial of tideglusib in Alzheimer's disease[J]. Journal of Alzheimer’s Disease, 2015, 45(1): 75-88.
[5] Luna-Medina R, Cortes-Canteli M, Sanchez-Galiano S, et al. NP031112, a thiadiazolidinone compound, prevents inflammation and neurodegeneration under excitotoxic conditions: potential therapeutic role in brain disorders[J]. Journal of Neuroscience, 2007, 27(21): 5766-5776.
[6] Mathuram, Theodore Lemuel et al. “Tideglusib induces apoptosis in human neuroblastoma IMR32 cells, provoking sub-G0/G1 accumulation and ROS generation.” Environmental toxicology and pharmacology vol. 46 (2016): 194-205.
[7] Serenó, L et al. “A novel GSK-3beta inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo.” Neurobiology of disease vol. 35,3 (2009): 359-67.
Tideglusib是一种强效、选择性且不可逆的非ATP竞争性糖原合成酶激酶-3（GSK-3）抑制剂，对GSK-3βWT和GSK-3βC199A的IC50分别为5nM和60nM [1]。GSK-3是一种丝氨酸/苏氨酸激酶，与葡萄糖调节、细胞凋亡、蛋白质合成、细胞信号传导、细胞运输、基因转录和细胞增殖等生物学过程相关联 [2]。Tideglusib能够抑制炎症和神经退行性病变，可用于治疗阿尔茨海默病 [3-4]。
在体外，Tideglusib（2.5μM; 24h）完全消除了谷氨酸诱导的星形胶质细胞和小胶质细胞培养物中TNF-α和COX-2的表达，并显著减少了膜联蛋白-V阳性细胞的数量，对皮质神经元有抗炎和神经保护作用 [5]。不同浓度的Tideglusib（5-120μM; 48h）剂量依赖性地降低了人类神经母细胞瘤(IMR32)的细胞活力 [6]。
在体内，Tideglusib（2ng/2.5μl PBS; stereotactic injection）治疗显著改善了kainic acid（KA）诱导的局灶性兴奋性毒性模型大鼠的脑损伤，并降低了星形胶质细胞和小胶质细胞中的TNF-α阳性染色 [5]。Tideglusib（200mg/kg/day; 3 months）口服治疗降低了APP/tau双转基因小鼠中tau蛋白磷酸化水平，减少淀粉样蛋白沉积和斑块相关的星形胶质细胞增殖，同时保护内嗅皮层和防止海马CA1区神经元死亡 [7]。
| Kinase experiment [1]: | |
Preparation Method | Kinase assay was carried out at 25°C in a final volume of 10μl in 384-well low volume round bottom black plates with 50mm Hepes, pH 7.5, 10mm MgCl2, 1mm EGTA, and 0.01% Brij-35 as assay buffer. Enzyme concentration ranged from 2 to 5nm. ATP and peptide concentrations were 12.5 and 2μm, respectively. The assays were run for 1h in the presence or absence of compounds in a final DMSO concentration of 1%, and samples were processed. When double titrations of ATP and Tideglusib were performed, varying both ATP and Tideglusib concentrations while keeping the concentration of peptide substrate fixed. Data analysis was performed by fitting the experimental data to the appropriate equations for competitive, uncompetitive, and non-competitive inhibition. |
Reaction Conditions | 0.1nM-1μM; 1h |
Applications | The IC50 value of Tideglusib in inhibiting GSK-3β is 5nm in the pre-incubation condition and 105nm in the non-pre-incubation condition. |
| Cell experiment [2]: | |
Cell lines | Rat primary astrocytes, microglia, and neurons |
Preparation Method | Tideglusib (2.5μm) was added to the culture medium of astrocytes and microglia 1 h before exposure to glutamate (500μm), cells were incubated for 24 h before tissue culture medium was collected, and the cells were evaluated for tumor necrosis factor-α (TNF-α) and cyclooxygenase type 2 (COX-2) expression. |
Reaction Conditions | 2.5μM; 24h |
Applications | Tideglusib completely abolished the expression of TNF-α and COX-2 in the astrocyte and microglial cell cultures induced by glutamate. |
| Animal experiment [2]: | |
Animal models | Wistar rats (focal excitotoxic model) |
Preparation Method | Each group of rats (n ≥ 5) was anesthetized by intraperitoneal injection of ketamine (60mg/kg) and Domtor (5μg/kg), and then placed in a stereotactic apparatus. kainic acid (KA) (1μg dissolved in 2.5μL PBS) or in combination with Tideglusib (2ng dissolved in 2.5μL PBS) was injected separately into the hippocampus. The control animals were injected with solvent. Each injection was administered using a micro-pump and lasted for more than 2.5 minutes. Afterward, these rats were housed individually for recovery care. Behavioral analysis was conducted. After stereotactic injection, the animals were anesthetized at different times and perfused with 4% paraformaldehyde solution via the heart. The brain was removed and placed in the same solution overnight at 4°C, subjected to cryoprotection in a 30% sucrose polyformaldehyde solution, frozen, and obtained 30μm coronal sections under a cryostat. The floating sections were processed with the diaminobenzidine method or double immunofluorescence analysis for Nissl staining or immunohistochemical treatment. |
Dosage form | 2ng/2.5μl PBS; stereotactic injection |
Applications | Tideglusib treatment significantly improved brain damage in rats, reduced the loss of hippocampal cells, and significantly decreased the TNF-α positive staining in astrocytes and microglia. |
References: | |
| Cas No. | 865854-05-3 | SDF | |
| 别名 | 4-苄基-2-(萘-1-基)-[1,2,4]噻二唑烷-3,5-二酮,NP031112 | ||
| 化学名 | 4-benzyl-2-naphthalen-1-yl-1,2,4-thiadiazolidine-3,5-dione | ||
| Canonical SMILES | C1=CC=C(C=C1)CN2C(=O)N(SC2=O)C3=CC=CC4=CC=CC=C43 | ||
| 分子式 | C19H14N2O2S | 分子量 | 334.39 |
| 溶解度 | ≥ 16.7 mg/mL in DMSO with gentle warming | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.9905 mL | 14.9526 mL | 29.9052 mL |
| 5 mM | 598.1 μL | 2.9905 mL | 5.981 mL |
| 10 mM | 299.1 μL | 1.4953 mL | 2.9905 mL |
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