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|
|Cell Lines||Hep 3B cells|
|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|
|Cell Lines||HCC Cell|
|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 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.|
|Incubation time||72-120 hours|
|Animal models||Mice bearing LIXC012 tumors|
|Formulation||0.5% carboxymethylcellulose/1% Tween 80 as a suspension|
|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||4 mg/mL warmed in DMSO|
Paralog-Specific Kinase Inhibition of FGFR4: Adding to the Arsenal of Anti-FGFR Agents.
Packer LM, et al. Cancer Discov. 2015 Apr;5(4):355-7. PMID: 25847957.
First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway.
Hagel M, et al. Cancer Discov. 2015 Apr;5(4):424-37. PMID: 25776529.
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FGF-401 is an inhibitor of FGFR4 extracted from patent WO2015059668A1, compound example 83; has an IC50 of 1.9 nM.
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H3B-6527 (H3 Biomedicine) is a highly selective FGFR4 inhibitor with potent antitumour activity in FGF19 amplified cell lines and mice.
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