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-KDRrelated 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. Cancer Res; 72(8); 2045-56. Ó2012 AACR.

Co-active receptor tyrosine kinases mitigate the effect of FGFR inhibitors in FGFR1-amplified lung cancers with low FGFR1 protein expression

“…Table 3). These results suggest FGFR1-gene amplification is important to predict sensitivity against FGFR inhibitors, and the apparent discrepancy may be a result of drug promiscuity; in contrast to NVP-BGJ398 and AZD4547 which are relatively selective pan-FGFR inhibitors 33,34 , Ponatinib inhibits a number of non-FGFR kinases with IC50 concentrations less than 10nM, including VEGFR, PDGFR, EPH receptors, SRC, KIT, and RET 35 .…”

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

“…AZD4547 suppresses FGFR signaling and growth in tumor cell lines owing to deregulated FGFR expression. In a representative FGFR3-driven human tumor xenograft model, the oral administration of AZD4547 was well tolerated and resulted in potent antitumor activity ( 72 ). AZD4547 is currently being evaluated in a phase I clinical trial.…”

Discovery of Substituted 1H-Pyrazolo[3,4-b]pyridine Derivatives as Potent and Selective FGFR Kinase Inhibitors

“…12,13 Thus, discovery of highly selective FGFR inhibitors is an unmet medical need. Currently, several selective FGFR inhibitors have progressed robustly into clinical trials, such as NVP-BGJ398, 14 AZD4547, 15 and CH5183284 16 (Figure 1). PD173074 (Figure 1), the first reported selective FGFR inhibitor, inhibits FGFR1 with an IC 50 value of 21.5 nM at the molecular level, while inhibiting PDGFR, c-Src and EGFR, as well as several serine/threonine kinases with 1000-fold or greater IC 50 values.…”

“…AZD4547 inhibits FGFR1−4 (IC 50 = 0.2, 2.5, 1.8, and 165 nM, respectively) with low nanomolar potency at the molecular level, while inhibiting VEGFR2 with an IC 50 value of 24 nM. 15 Based on these findings, we wished to explore new scaffolds based on the structure of AZD4547, which had higher potency and higher selectivity for FGFR over VEGFR2 than AZD4547. By utilizing the scaffold hopping strategy and incorporation of chlorines at the 2-and 6-positions of the phenyl ring, we designed novel 1H-pyrazolo [3,4-b]pyridine scaffold derivatives (Figure 2), which demonstrated excellent in vitro and in vivo antitumor activities and high selectivity for FGFR over VEGFR2.…”