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|
|Cell Lines||H1581 (FGFR1 WT or V561M) cells|
|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 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.|
|Incubation time||12 h|
|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||DMSO: 10 mg/mL|
Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors.
Tan L, et al. Proc Natl Acad Sci U S A. 2014 Nov 11;111(45):E4869-77. PMID: 25349422.
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