Description
AZD4547 is a novel selective FGFR inhibitor targeting FGFR1/2/3 with IC50 of 0.2 nM/2.5 nM/1.8 nM in cell-free assays, weaker activity against FGFR4, VEGFR2(KDR), and little activity observed against IGFR, CDK2, and p38. Phase 2/3.
Features
Greater selectivity for FGFR1-3 over FGFR4. AZD4547 is active against the tyrosine kinase activity of both the wild-type and mutant forms of FGFR.
In vitro
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.
In vivo
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.
Description
AZD 4547 is a selective inhibitor of the fibroblast growth factor receptor (FGFR) tyrosine kinase with IC
50 values of 0.2, 2.5, and 1.8 nM for FGFR1, 2, and 3, respectively. It displays weaker activity against FGFR4 (IC
50 = 165 nM), VEGFR2 (IC
50 = 24 nM), and a panel of other tyrosine and serine/theronine kinases such as insulin-
like growth factor 1 receptor (IC
50 = 581 nM), cyclin-
dependent kinase 2 (IC
50 = >10 μM), and p38 (IC
50 = >100 μM). AZD 4547 has demonstrated antiproliferative activity in tumor cell lines expressing deregulated FGFRs (IC
50s = 18-
281 nM). In an FGFR-
driven human tumor xenograft mouse model, oral administration of AZD 4547 at concentrations up to 12.5 mg/kg/day resulted in potent dose-
dependent antitumor activity.
Chemical Properties
Pale Yellow Solid
Uses
AZD4547 is a bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor (FGFR) tyrosine kinases. AZD4547 is particularly effective in inhibiting FGFR1, 2, and 3 tyrosine k
inases and is under clinical investigation for the treatment of FGFR-dependent tumors.
Definition
ChEBI: AZD4547 is a member of the class of benzamides that is a carboxamide resulting from the formal condensation of the carboxy group of 4-(cis-3,5-dimethylpiperazin-1-yl)benzoic acid with the amino substituent of 5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-amine. It is an inhibitor of the fibroblast growth factor receptor (FGFR). It has a role as a fibroblast growth factor receptor antagonist. It is a member of pyrazoles, a N-arylpiperazine and a member of benzamides.
