Abstract 3568: Characterization of AZD4547: An orally bioavailable, potent and selective inhibitor of FGFR tyrosine kinases 1, 2 and 3

Abstract

Abstract The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signalling axis plays an important role in normal organ, vascular and skeletal development. Deregulation of FGFR signalling through genetic modification or over-expression of the receptors (or their ligands) has been observed in numerous tumour settings, whilst the FGF/FGFR axis also plays a key role in driving tumor angiogenesis. A growing body of data demonstrates that inhibition of FGFR signalling can result in anti-proliferative and/or pro-apoptotic effects, both in vitro and in vivo, thus confirming the validity of FGFR as a therapeutic target. AZD4547 is a small molecule inhibitor which competes with ATP for binding to FGF receptors 1, 2 and 3, thus inhibiting autophosphorylation and downstream signalling. Using in vitro kinase assays, we demonstrate that AZD4547 is a potent inhibitor of FGFR's 1,2 and 3 with IC50 values of 0.2, 2.5 and 1.8nM respectively. AZD4547 is also highly selective vs a panel of over 70 other kinases (no activity at 10μM) and importantly vs Kinase Insert Domain Receptor (KDR) (>120-fold window in cellular assays vs. FGFR2). In vitro treatment of a large panel of cell lines (>100) with AZD4547 resulted in varying anti-proliferative responses, the most potent of which were almost exclusively confined to those cell-lines in which FGFR signalling was de-regulated. Treatment of these sensitive cell lines with AZD4547 for 1hr, demonstrated potent inhibition of phosphorylation of FGF receptors and downstream substrates including p44/42 MAPK. The anti-proliferative effects of AZD4547 appear to be cell line dependent and vary between potent G1-phase cell cycle arrest and apoptotic induction. Chronic in vivo dosing of AZD4547 up to 12.5mg/kg qd was well tolerated and resulted in dose-dependent growth inhibition in a KMS11 tumour xenograft model. This in vivo anti-tumor activity is correlated with exposure to AZD4547 and associated pharmacodynamic modulation of phospho-FGFR. These data confirm the novelty of AZD4547 as a potent and selective agent for the therapeutic treatment of tumors with deregulated FGF/FGFR signalling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3568. doi:10.1158/1538-7445.AM2011-3568