CHIR-99021 exhibits >500-fold selectivity for GSK-3 over closely related kinases. CHIR-99021 also displays >800-fold selectivity against 45 additional enzymes and receptors. CHIR-99021 (3 μM) increases free cytosolic β-catenin by 1.9-fold, mimicking the canonical Wnt signaling pathway in 3T3-L1 preadipocytes. CHIR-99021 promotes primary beta cell replication in isolated rat islets at concentrations as low as 1 μM, with 2-3 fold increase of cell replication at 5 μM of CHIR-99021 treatment. Oral administration of CHIR-99021 at 16 or 48 mg/kg 1 hour before oral glucose challenges in ZDF rats significantly improves glucose tolerance with 14% and 33% reduction in plasma glucose at 16 mg/kg and 48 mg/kg, respectively, and the higher dose of CHIR-99021 also reduces hyperglycemia before the oral glucose challenge.
|Cell lines||CHO-IR cells|
|Preparation method||GS activity assays.
CHO-IR cells expressing human insulin receptor, (provided by Hans Bos) were grown to 80% confluence in Hamm’s F12 medium with 10% fetal bovine serum and without hypoxanthine (34). Trypsinized cells were seeded in 6-well plates at 1 × 106 cells/well in 2 ml of medium without fetal bovine serum. After 24 h, medium was replaced with 1 ml of serum-free medium containing GSK-3 inhibitor or control (final DMSO concentration <0.1%) for 30 min at 37°C. Cells were lysed by freeze/thaw in 50 mmol/l tris (pH 7.8) containing 1 mmol/l EDTA, 1 mmol/l DTT, 100 mmol/l NaF, 1 mmol/l phenylmethylsulfonyl fluoride, and 25 μg/ml leupeptin (buffer A) and centrifuged 15 min at 4°C/14000g. The activity ratio of GS was calculated as the GS activity in the absence of glucose-6-phosphate divided by the activity in the presence of 5 mmol/l glucose-6-phosphate, using the filter paper assay of Thomas et al.
|Animal models||fasting ZDF rats|
|Formulation||20 mmol/l citrate-buffered 15% Captisol or suspensions in 0.5% carboxymethylcellulose|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 90 mg/mL
Water 6 mg/mL
Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo.
Ring DB, et al. Diabetes. 2003 Mar;52(3):588-95. PMID: 12606497.
|Related GSK-3 Products|
IM-12 is a potent and selective GSK-3β inhibitor with IC50 of 53 nM, which also enhances canonical Wnt signalling.
SB415286 is a potent GSK3α inhibitor with IC50/Ki of 78 nM/31 nM with equally effective inhibition of GSK-3β.
TDZD-8 is a non-ATP competitive GSK-3β inhibitor with IC50 of 2 μM; minimal inhibitory effect observed on CDK1, casein kinase II, PKA and PKC.
LY2090314 is a potent GSK-3 inhibitor for GSK-3α/β with IC50 of 1.5 nM/0.9 nM; may improve the efficacy of platinum-based chemotherapy regimens. Phase 1/2.
AZD1080 is a selective, orally active, brain permeable GSK3 inhibitor, inhibits human GSK3α and GSK3β with Ki of 6.9 nM and 31 nM, respectively.
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