FIIN-3 is the first inhibitor that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. FIIN-3 potently inhibits both WT FGFRs (EC50 in the 1- to 41-nM range) and the gatekeeper mutant of FGFR2 (EC50 of 64 nM). FIIN-3 also strongly inhibits EGFR, with an EC50 of 43 nM.
FIIN-3 shows even better activity against EGFR mutant L858R (EC50 of 17 nM) and moderate activity, displaying an EC50 of 231 nM, against the EGFR mutant L858R/T790M mutant. In WT FGFR2 Ba/F3 cells, FIIN-3 completely inhibits the FGFR2 autophosphorylation on Tyr656/657 at concentrations as low as 3 nM. In FGFR2 V564M Ba/F3 cells, FIIN-3 is capable of inhibiting the FGFR2 mutant V564M autophosphorylation with partial inhibition at 100 nM and complete inhibition observed at 300 nM.
 |
Source | Proc Natl Acad Sci U S A (2014 Nov). Figure 4. FIIN-3 |
| Method | Western blot | |
| Cell Lines | H1581 (FGFR1 WT or V561M) cells | |
| Concentrations | 1.0 µM | |
| Incubation Time | 12 h | |
| Results | The downstream prosurvival signaling pathways of FGFR also were examined in these cell lines, showing that FIIN-2, FIIN-3, and BGJ398 effectively suppressed p-FRS2, p-FGFR, p-AKT, and p-ERK in these FGFR-activated cells at 1.0 µM, except that BGJ398 failed in the FGFR1 V561M H1581 cells. In H1581 cells they also inhibited FGFR V561M in a dose-responsive manner, with both of them inhibiting most autophosphorylation of FGFR1 V561M at 333 nM, whereas BGJ398 still was inactive at 1.0 µM. |
| Cell Experiment | |
|---|---|
| Cell lines | H1581 (FGFR1 WT or V561M) cells |
| Preparation method | Inhibition of FGFR-dependent signaling by BGJ398, FIIN-2, and FIIN-3 in H1581 (FGFR1 WT or V561M) cells. Cells were treated with indicated inhibitors at 1.0 µM for 12 h and then were lysed and subjected to Western blot for the indicated proteins or phosphoproteins. |
| Concentrations | 1.0 µM |
| Incubation time | 12 h |
| Animal Experiment | |
|---|---|
| Animal models | |
| Formulation | |
| Dosages | |
| Administration | |
| Molecular Weight | 691.61 |
| Formula | C34H36Cl2N8O4 |
| CAS Number | 1637735-84-2 |
| Solubility (25°C) | DMSO: 10 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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