ZD6474 [N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-
amine]is a potent, p.o. active, low molecular weight inhibitor of
kinase insert domain-containing receptor [KDR/
vascular endothelial growth factor receptor (VEGFR) 2]
tyrosine kinase activity (IC(50) = 40 nM). This compound has some additional activity versus the
tyrosine kinase activity of
fms-like tyrosine kinase 4 (VEGFR3;IC(50) = 110 nM) and
epidermal growth factor receptor (EGFR/HER1; IC(50) = 500 nM) and yet demonstrates selectivity against a range of other
tyrosine and
serine-threonine kinases. The activity of
ZD6474 versus
KDR tyrosine kinase translates into potent inhibition of
vascular endothelial growth factor-A (
VEGF)-stimulated endothelial cell (human umbilical vein endothelial cell) proliferation in vitro (IC(50) = 60 nM). Selective inhibition of
VEGF signaling has been demonstrated in vivo in a
growth factor-
induced hypotension model in anesthetized rat: administration of
ZD6474 (2.5 mg/kg, i.v.) reversed a hypotensive change induced by
VEGF (by 63%) but did not significantly affect that induced by
basic fibroblast growth factor. Once-daily
oral administration of
ZD6474 to growing rats for 14 days produced a dose-dependent increase in the femoro-tibial epiphyseal growth plate zone of
hypertrophy, which is consistent with inhibition of
VEGF signaling and angiogenesis in vivo. Administration of 50 mg/kg/day
ZD6474 (once-daily, p.o.) to athymic mice with intradermally implanted A549
tumor cells also inhibited
tumor-induced neovascularization significantly (63% inhibition after 5 days; P < 0.001).
Oral administration of
ZD6474 to athymic mice bearing established (0.15-0.47 cm(3)), histologically distinct (lung, prostate, breast, ovarian, colon, or vulval) human
tumor xenografts or after implantation of aggressive syngeneic rodent
tumors (lung,
melanoma) in immunocompetent mice, produced a dose-dependent inhibition of
tumor growth in all cases. Statistically significant antitumor activity was evident in each model with at least 25 mg/kg
ZD6474 once daily (P < 0.05, one-tailed t test). Histological analysis of Calu-6
tumors treated with 50 mg/kg/day
ZD6474 for 24 days showed a significant reduction (>70%) in CD31 (endothelial cell) staining in nonnecrotic regions.
ZD6474 also restrained growth of much larger (0.9 cm(3) volume) Calu-6 lung
tumor xenografts and induced profound regression in established PC-3 prostate
tumors of 1.4 cm(3) volume.
ZD6474 is currently in Phase I clinical development as a once-daily oral
therapy in patients with advanced
cancer.