title: AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family.
abstract: 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 pharmacologic 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.
authors.affiliation: AstraZeneca Innovation Center China, Building 7, 898 Halei Road, Zhangjiang Hi-Tech Park, Shanghai 201203, PR China. paul.gavine@astrazeneca.com
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gavine
authors.forename: Lorraine
authors.initials: L
authors.lastname: Mooney
authors.forename: Elaine
authors.initials: E
authors.lastname: Kilgour
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Thomas
authors.forename: Katherine
authors.initials: K
authors.lastname: Al-Kadhimi
authors.forename: Sarah
authors.initials: S
authors.lastname: Beck
authors.forename: Claire
authors.initials: C
authors.lastname: Rooney
authors.forename: Tanya
authors.initials: T
authors.lastname: Coleman
authors.forename: Dawn
authors.initials: D
authors.lastname: Baker
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Mellor
authors.forename: A Nigel
authors.initials: AN
authors.lastname: Brooks
authors.forename: Teresa
authors.initials: T
authors.lastname: Klinowska
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001549:Benzamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D011720:Pyrazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*
chemical_list: C572463:AZD4547; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D017468:Receptors, Fibroblast Growth Factor