CHIR-99021 (Laduviglusib)

N.º de catálogoS1263 Lote:S126308

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Datos técnicos

Fórmula

C22H18Cl2N8
Peso molecular 465.34 Número CAS 252917-06-9
Solubilidad (25°C)* In vitro DMSO 93 mg/mL (199.85 mM)
Water Insoluble
Ethanol Insoluble
In vivo (Agregue los solventes al producto individualmente y en orden.)
Homogeneous suspension
CMC-NA
≥5mg/ml Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
* <1 mg/ml significa ligeramente soluble o insoluble.
* Tenga en cuenta que Selleck prueba la solubilidad de todos los compuestos internamente, y la solubilidad real puede diferir ligeramente de los valores publicados. Esto es normal y se debe a ligeras variaciones entre lotes.
* Envío a temperatura ambiente (Las pruebas de estabilidad demuestran que este producto se puede enviar sin medidas de refrigeración.)

Preparación de soluciones madre

Actividad biológica

Descripción Laduviglusib (CHIR-99021, CT99021) es un inhibidor de GSK-3α y GSK-3β con valores de IC50 de 10 nM y 6.7 nM, respectivamente. No exhibe reactividad cruzada contra las quinasas dependientes de ciclina (CDK) y muestra una selectividad 350 veces mayor hacia GSK-3β en comparación con las CDK. Este compuesto funciona como un activador de Wnt/β-catenin e induce la autophagy.
Objetivos
GSK-3β
(Cell-free assay)		 GSK-3α
(Cell-free assay)
6.7 nM 10 nM
In vitro CHIR-99021 (Laduviglusib) shows greater than 500-fold selectivity for GSK-3 versus its closest homologs CDC2 and ERK2, as well as other protein kinases. Furthermore, it shows only weak binding to a panel of 22 pharmacologically relevant receptors and little inhibitory activity against a panel of 23 nonkinase enzymes. This compound induces the activation of glycogen synthase (GS) in insulin receptor-expressing CHO-IR cells with EC50 of 0.763 μM.
In vivo Oral administration of CHIR-99021 (Laduviglusib) at 30 mg/kg enhances glucose metabolism in a rodent model of type 2 diabetes, with a maximal plasma glucose reduction of nearly 150 mg/dl 3-4 hours after administration, while plasma insulin remains at or below control levels. When given orally at 16 or 48 mg/kg 1 hour before oral glucose challenges in ZDF rats, this compound significantly improves glucose tolerance with 14% and 33% reduction in plasma glucose at 16 mg/kg and 48 mg/kg, respectively; the higher dose also reduces hyperglycemia before the oral glucose challenge.

Protocolo (de referencia)

Ensayo celular:

[1]
  • Líneas celulares

    Insulin receptor–expressing CHO-IR cells; Primary rat hepatocytes

  • Concentraciones

    0.01-10 μM

  • Tiempo de incubación

    30 min

  • Método

    CHIR-99021 (Laduviglusib) is used in the following procedure: CHO-IR cells expressing human insulin receptor are grown to 80% confluence in Hamm’s F12 medium with 10% fetal bovine serum and without hypoxanthine. Trypsinized cells are seeded in 6-well plates at 1 × 10⁶ cells/well in 2 ml of medium without fetal bovine serum. After 24 h, medium is replaced with 1 ml of serum-free medium containing this compound or control (final DMSO concentration <0.1%) for 30 min at 37°C. Cells are lysed and centrifuged 15 min at 4°C/14000g. The activity ratio of GS is 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.
Estudio en animales:

[1]
  • Modelos animales

    Female db/db mice; Male ZDF rats

  • Dosificaciones

    8-48 mg/kg

  • Administración

    oral administration

Referencias

  • https://pubmed.ncbi.nlm.nih.gov/12606497/

Validación de productos por parte del cliente

<p>For MTT assays, cells (2,000 ~ 5,000 cells/well) were subcultured into 96-well plates according to their growth properties. Cell proliferation was assayed at 72 hr after treatment of CHIR-99021 by adding 20 μl of 5 mg/ml 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) solution per 100 μl of growth medium. After incubating for 3-4 h at 37°C, the media were removed and 150 µl/well of MTT solvent (either absolute DMSO or isopropanol containing 4 mM HCl and 0.1% Nonidet-40) was added to dissolve the formazan. The absorbance of each well was measured by ELx808 (BioTek, Winooski, VT) or Wallac Victor2 (Perkin-Elmer Life Sciences, Boston, MA) Microplate Reader. Viable cells are presented as percent of control, vehicle-treated cells. </p>

, , Dr. Yong-Weon Yi from Georgetown University Medical Center

Lu1205 were treated with protein kinase inhibitors. Cell cycle protein expression was analyzed by western blot.

Datos de [ , , Med Oncol, 2017, 35(1):7 ]

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