AZD4547

A potent and selective inhibitor of FGFR1/2/3 with IC50s of 0.2/1.8/2.5 nM; shows weak acticity against KDR (IC50=24 nM), FGFR4 (IC50=165 nM) and IGFR (IC50=581 nM), and on activity against CDK2, Axl, FAK, p38 etc.; suppresses FGFR signaling and growth in tumor cell lines with deregulated FGFR expression; orally bioavailable.Lung Cancer Phase 2 Clinical (In Vitro) :AZD4547 also inhibits recombinant VEGFR2 (KDR) kinase activity with an IC50 of 24 nM. In KG1a, Sum52-PE, MCF7, and KMS11 cell lines, AZD4547 potently inhibits autophosphorylation of FGFR1, 2, and 3 tyrosine kinases (IC50 values of 12, 2, and 40 nM, respectively) and displays weaker inhibition of FGFR4 cellular kinase activity (IC50=142 nM) . Significantly weaker inhibitory activity is observed versus cellular KDR and IGFR ligand-induced phosphorylation (IC50 values of 258 and 828 nM, respectively), representing approximately 20- and 70-fold selectivity over cellular FGFR1. Besides, AZD4547 potently inhibits FGFR phosphorylation and downstream signaling affected through FRS2, PLCγ, and MAPK at the cellular level. (In Vivo) :Female SCID mice bearing KMS11 tumors are randomized and treated chronically with AZD4547 at a range of well-tolerated doses. Oral AZD4547 treatment results in dose-dependent tumor growth inhibition. Twice daily administration of AZD4547 at 3 mg/kg gives statistically significant tumor growth inhibition of 53% (P<0.0005 by one-tailed t test) when compare with vehicle-treated controls, whereas doses of 12.5 mg/kg once daily and 6.25 mg/kg twice daily results in complete tumor stasis (P<0.0001) . A further efficacy study in the KG1a model with 12.5 mg/kg once daily AZD4547 results in 65% tumor growth inhibition (P=0.002) .