TG101209, an orally bioavailable JAK2 inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. TG101209 potently inhibits JAK2 (IC(50)=6 nM), FLT3 (IC(50)=25 nM) and RET (IC(50)=17 nM) kinases, with significantly less activity against other tyrosine kinases including JAK3 (IC(50)=169 nM). TG101209 also inhibited STAT3 activation and survivin expression, and sensitized HCC2429 (DER=1.34, p=0.002) and H460 (DER=1.09, p=0.006) cells to radiation in clonogenic assays. In vivo, addition of TG101209 to radiation in lung xenografts produced a significant tumor growth delay (>10 days). TG101209 has significant in vitro activity in multiple myeloma and displays preferential cytotoxicity for CD45+ myeloma cells.
 |
Source | J Thorac Oncol (2011). Figure 1.TG101209 |
| Method | western blots | |
| Cell Lines | HCC2429 and H460 lung cancer cells | |
| Concentrations | 1 or 3 μM | |
| Incubation Time | 24 or 48 h | |
| Results | 1 μM and 3 μM TG101209 reduced phospho- STAT3 in both cell lines while total STAT3 remained constant throughout with only a minor reduction after treatment with 3 μM TG101209 for 48 h. |
| Cell Experiment | |
|---|---|
| Cell lines | Ba/F3 cells, MPLW515L, CTLL-2 cells and HEL and K562 cells |
| Preparation method | XTT assay for cell proliferation. In brief, approximately 2*103 cells were plated into microtiterplate wells in 100 ml RPMI-1640 growth media with indicated concentrations of inhibitor. The relative growth of cells was quantified at 24-h intervals using Cell Proliferation Kit II (XTT) as per manufacturer’s guidelines (Roche, Indianapolis, IN, USA). After incubation, 20 ml of XTT was added to the wells and allowed to incubate for 4–6 h. The colored formazan product was measured spectrophotometrically at 450 nm with correction at 650 nm, and IC50 values were determined using the GraphPad Prism 4.0 software. Data were subjected to a non-linear regression-fit analysis and IC50 values were determined as the concentration, that inhibited proliferation by 50%. All experiments were done in triplicate and the results normalized to growth of untreated cells. |
| Concentrations | 0~100 μ M |
| Incubation time | 24 h |
| Animal Experiment | |
|---|---|
| Animal models | JAK2V617F-induced hematopoietic disease in a nude mouse model |
| Formulation | DMSO |
| Dosages | 10, 30 and 100mg/kg bid |
| Administration | oral gavage |
| Molecular Weight | 509.67 |
| Formula | C26H35N7O2S |
| CAS Number | 936091-14-4 |
| Solubility (25°C) | DMSO 72 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
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