In vitro: In MDA-MB-453 cells, BLU9931 potently inhibits phosphorylation of FGFR4 signaling pathway. BLU9931 inhibits proliferation of HCC cell lines that express an intact FGFR4 signaling complex, such as Hep 3B, HUH-7, and JHH-7 cell lines, with EC50 of <1 μM. BLU9931 also inhibits proliferation in PDX-derived cell lines with an intact FGFR4 signaling pathway.
In vivo: In mice bearing the FGF19-amplified Hep 3B liver tumors, BLU9931 (300 mg/kg, p.o.) leads to tumor regression and prevents this weight loss induced by tumors. In mice bearing the FGF19-overexpressing PDX-derived LIXC012 xenografts, treatment with BLU9931 (300 mg/kg, p.o.) also leads to tumor regression.
 |
Source | Cancer Discov (2015). Figure 3. BLU-9931 |
| Method | qRT-PCR | |
| Cell Lines | Hep 3B cells | |
| Concentrations | 100 nmol/L | |
| Incubation Time | 1 h | |
| Results | Consistent with this model, we observed an induction of CYP7A1 expression for at least 8 hours following the removal of BLU9931 |
 |
Source | Cancer Discov (2015). Figure 2. BLU-9931 |
| Method | Western Blot | |
| Cell Lines | HCC Cell | |
| Concentrations | 100 ng/mL | |
| Incubation Time | 1 h | |
| Results | In contrast, LY-2874455 and BGJ398 demonstrated very potent dose-dependent inhibition of phosphorylated FGFR (pFGFR), pFRS2, pMAPK, and pAKT |
| Cell Experiment | |
|---|---|
| Cell lines | Hep 3B, HUH-7, JHH-7, PLC/PRF/5, SK-HEP-1, SNU-182, SNU-387, SNU-398, SNU-423, SNU-449, SNU-878 cells |
| Preparation method | Established and PDX-derived HCC cell lines are seeded in 96-well plates in respective growth media, allowed to attach overnight, and treated with a dilution series of test compounds for two cell-doubling times. Cell viability is determined by CellTiter-Glo, and results represented as background-subtracted relative light units normalized to a DMSO-treated control. Relative EC50 values are determined at 50% inhibition between the top and bottom plateau of the dose–response curve. |
| Concentrations | ~10 μM |
| Incubation time | 72-120 hours |
| Animal Experiment | |
|---|---|
| Animal models | Mice bearing LIXC012 tumors |
| Formulation | 0.5% carboxymethylcellulose/1% Tween 80 as a suspension |
| Dosages | ~300 mg/kg |
| Administration | p.o. |
| Molecular Weight | 509.38 |
| Formula | C26H22Cl2N4O3 |
| CAS Number | 1538604-68-0 |
| Solubility (25°C) | 4 mg/mL warmed in DMSO |
| 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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