AZD4547: An orally bioavailable, potent and selective inhibitor of the Fibroblast Growth Factor Receptor tyrosine kinase family
Menée in vitro et in vivo, cette étude évalue l'activité antitumorale d'un composé appelé AZD4547, un inhibiteur de l'activité kinase du récepteur du facteur de croissance des fibroblastes
The fibroblast growth factor (FGF) signaling axis is increasingly implicated in tumorigenesis and chemoresistance. Several small molecule FGF-receptor (FGFR) kinase inhibitors are currently in clinical development, however, the predominant activity of the most advanced of these agents is against the kinase insert domain receptor (KDR), which compromises the FGFR selectivity. Here we report the pharmacological profile of AZD4547, a novel and selective inhibitor of the FGFR1, 2 and 3 tyrosine kinases. AZD4547 inhibited recombinant FGFR kinase activity in vitro and suppressed FGFR signaling and growth in tumor cell lines with deregulated FGFR expression. In a representative FGFR-driven human tumor xenograft model, oral administration of AZD4547 was well tolerated and resulted in potent dose-dependent antitumor activity, consistent with plasma exposure and pharmacodynamic modulation of tumor FGFR. Importantly, at efficacious doses, no evidence of anti-KDR related effects were observed, confirming the in vivo FGFR selectivity of AZD4547. Taken together, our findings show that AZD4547 is a novel selective small molecule inhibitor of FGFR with potent antitumor activity against FGFR deregulated tumors in preclinical models. AZD4547 is under clinical investigation for the treatment of FGFR-dependent tumors.