AZD4547 1035270-39-3

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Molecular Weight:

463.57 AZD4547 is a novel selective FGFR Inhibitor targeting FGFR1/2/3 with IC50 of 0.2 nM/2.5 nM/1.8 nM, weaker activity against FGFR4, VEGFR2(KDR), and little activity observed against IGFR, CDK2, and p38. Phase 2/3.


Biological Activity


Compared to FGFR1-3, AZD4547 displays weaker activity against FGFR4 with
IC50 of 165 nM. AZD4547 only inhibits recombinant VEGFR2 (KDR) kinase
activity with IC50 of 24 nM, in the in vitro selectivity test against a
diverse panel of representative human kinases. AZD4547 at 0.1 μM
exhibits no activity against a range of recombinant kinases including
ALK, CHK1, EGFR, MAPK1, MEK1, p70S6K, PDGFR, PKB, Src, Tie2, and
PI3-kinase.


Consistently, the potent selectivity of AZD4547 for FGFR1-3
over FGFR4, IGFR, and KDR is also observed in cellular phosphorylation
assays. AZD4547 has potent in vitro antiproliferative activity only
against tumor cell lines expressing deregulated FGFRs such as KG1a,
Sum52-PE, and KMS11 with IC50 of 18-281 nM, and is inactive against MCF7
as well as more than 100 additional tumor cell lines.


AZD4547 treatment
potently inhibits FGFR and MAPK phosphorylation in human tumor cell
lines in a dose-dependent manner. AZD4547 also potently inhibits the
phosphorylation of FRS2 and PLCγ, downstream markers of FGFR signaling.
Notably, AZD4547 affects the AKT phosphorylation in the breast cell
lines, MCF7 and Sum52-PE but not in KG1a and KMS11 lines. AZD4547
treatment significantly induces Apoptosis in Sum52-PE and KMS11 cells,
dramatically increases G1 arrest but not apoptosis in KG1a cells, and
has no effect on Cell Cycle distribution or apoptosis in MCF7 cells.


Oral administration of AZD4547 at 3 mg/kg twice daily in mice bearing
KMS11 tumors results in significant tumor growth inhibition of 53% when
compared with vehicle-treated controls, and AZD4547 at 12.5 mg/kg once
daily or 6.25 mg/kg twice daily leads to complete tumor stasis, which is
associated with dose proportional pharmacodynamic modulation of
phospho-FGFR3 and reduced KMS11 tumor cell proliferation.


Moreover, oral
administration of AZD4547 at 12.5 mg/kg once daily results in 65% tumor
growth inhibition in the FGFR1-fusion KG1a xenograft model. At
efficacious dose levels, AZD4547 does not exhibit antiangiogenic
effects. AZD4547 has no significant effect on blood pressure and
therefore lacks in vivo anti-KDR activity. Consistently, dosing of 6.25
mg/kg orally twice daily AZD4547 is inactive in the cediranib-sensitive
xenograft models including Calu-6, HCT-15 and LoVo.






Method


Cells are exposed to various concentrations of AZD4547 for 72 hours. The
antiproliferative IC50 values are obtained by MTS proliferation assay.
For fluorescence-activated cell sorting (FACS), cells are fixed with 70%
ethanol and then incubated with propidium iodide/RNase A labeling
solution. Cell cycle profiles are assessed with a FACSCalibur instrument
and CellQuest analysis software.


For apoptotic analysis, cells and
media are gently harvested and centrifuged, followed by washing of cell
pellets. Cells are then processed for Annexin V-fluorescein
isothiocyanate (FITC) staining and propidium iodide uptake. The
proportion of cells staining positive for Annexin V are then assessed
with a FACSCalibur instrument and quadrant sorting is done by CellQuest
analysis software.

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Product Categories : Protein Tyrosine Kinase > FGFR Inhibitor