Abstract DDT01-01: Preclinical profile of AZD4547: A selective inhibitor of FGF-receptors 1, 2, and 3

Abstract

Abstract The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling axis comprises 18 ligands which exert their actions via 4 transmembrane tyrosine kinase receptors. FGFs signaling though their cognate receptors play an important role in normal organ, vascular and skeletal development. Deregulation of FGFR signaling through genetic modification or overexpression of the receptors (or their ligands) has been observed in numerous tumor settings, whilst the FGF/FGFR axis also plays an important role in driving tumor angiogenesis. A growing body of data demonstrates that inhibition of FGFR signaling can result in antiproliferative and/or proapoptotic effects, both in vitro and in vivo, thus confirming the validity of FGFR as a cancer 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 signaling. 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 1.8 nM respectively. AZD4547 is also highly selective vs. a panel of over 70 other kinases (no activity at 10 μM) 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, representing several tumor types) with AZD4547 resulted in varying antiproliferative responses, the most potent of which were almost exclusively confined to those cell-lines in which FGFR signaling was deregulated by either gene amplification, mutation or translocation. Treatment of these sensitive cell lines with AZD4547 for 1 hr, demonstrated potent inhibition of phosphorylation of FGF receptors and downstream substrates including pFRS2α and p44/42 MAPK. The antiproliferative 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 12.5 mg/kg qd was well tolerated and resulted in dose-dependent growth inhibition in KMS11 (FGFR3 translocated, multiple myeloma) and Snu16 (FGFR2 amplified, gastric) tumour xenograft models. This in vivo antitumor activity is correlated with exposure to AZD4547 and associated pharmacodynamic modulation of phospho-FGFR and downstream substrates. In addition to the single-agent efficacy, combining of AZD4547 with cytotoxic agents, currently used for the treatment of gastric cancer patients, revealed enhanced growth inhibition of Snu-16 xenografts. Collectively, these data confirm the suitability of AZD4547 as a potent and selective agent for the therapeutic treatment of tumors with deregulated FGF/FGFR signaling. 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 DDT01-01. doi:10.1158/1538-7445.AM2011-DDT01-01