A selective inhibitor of GSK3β
TDZD-8 is an inhibitor of glycogen synthase kinase-3β (GSK-3β) with IC50 value of 1.4μM [1].
TDZD-8 is a potent inhibitor of GSK-3β. It is found to act as a noncompetitive inhibitor of ATP binding. TDZD-8 is selective against GSK-3β over other protein kinases including PKA, casein kinase II and cyclin dependent kinase 1 (Cdk-1/cyclin B). However, it is also reported that TDZD-8 can inhibit the protein kinase C isoforms PKCβI and PKCδ with IC50 values of 1.4μM and 1.1μM, respectively [1, 2].
In cellular assay, TDZD-8 is found to decrease PDT-induced necrosis of neurons and decrease PDT-induced apoptosis of glial cells through inhibiting GSK-3β as well as PKC. Besides that, TDZD-8 also has anti-leukemia activity in many primary human leukemia cells. It is probably due to its inhibition of PKC and FLT3 [3].
参考文献:
[1] Komandirov M A, Knyazeva E A, Fedorenko Y P, et al. On the role of phosphatidylinositol 3-kinase, protein kinase b/Akt, and glycogen synthase kinase-3β in photodynamic injury of crayfish neurons and glial cells. Journal of Molecular Neuroscience, 2011, 45(2): 229-235.
[2] Martinez A, Alonso M, Castro A, et al. First non-ATP competitive glycogen synthase kinase 3 β (GSK-3β) inhibitors: thiadiazolidinones (TDZD) as potential drugs for the treatment of Alzheimer's disease. Journal of medicinal chemistry, 2002, 45(6): 1292-1299.
[3] Guzman M L, Li X, Corbett C A, et al. Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl, 2-methyl, 1, 2, 4-thiadiazolidine, 3, 5 dione (TDZD-8). Blood, 2007, 110(13): 4436-4444.
Kinase experiment: | GSK-3 activity is assayed in 50 mM Tris-HCl, pH 7.5, 10 mM MgCl2, 1 mM EGTA, and 1 mM EDTA buffer, at 37°C, in the presence of 15 μM GS-1 (substrate), 15 μM [γ-32P]ATP in a final volume of 12 μL. After 20 min incubation at 37°C, 4 μL aliquots of the supernatant are spotted onto 2×2 cm pieces of Whatman P81 phosphocellulose paper, and 20 s later, the filters are washed four times (for at least 10 min each time) in 1% phosphoric acid. The dried filters are transferred into scintillation vials, and the radioactivity is measured in a liquid scintillation counter. Blank values are subtracted, and the GSK-3β activity is expressed in picomoles of phosphate incorporated in GS-1 per 20 min or in percentage of maximal activity[1]. |
Animal experiment: | Apomorphine hydrochloride is administered (0.5?mg/kg). L-dopa (25?mg/kg) plus benserazide-HCl (6.25?mg/kg) are given once-daily. TDZD8, a non-ATP competitive inhibitor of GSK-3β, is dissolved in 10% DMSO and is administered i.p. (TDZD8-L group, 1?mg/kg; TDZD8-H group, 2?mg/kg, respectively) 30?min prior to L-dopa intake for 3 weeks. (±)-1-Phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF38393), a D1 Dopamine receptor agonist, is dissolved in saline and is administered i.p. (SKF38393-L group, 5?mg/kg; SKF38393-H group, 10?mg/kg, respectively) 30?min prior to L-dopa intake for 3 weeks[2]. |
参考文献: [1]. Martinez A, et al. First non-ATP competitive glycogen synthase kinase 3 beta (GSK-3beta) inhibitors: thiadiazolidinones (TDZD) as potential drugs for the treatment of Alzheimer's disease. J Med Chem. 2002 Mar 14;45(6):1292-9. | |
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