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Vol. 286, Issue 1, 569-577, July 1998
Departments of
Vascular and Cardiac Diseases (R.L.P., G.H.L.,
T.K.D., B.L.B.) and
Chemistry (C.C., J.M.H.), Parke-Davis
Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor,
Michigan; and
Division of Immunology and Cell Biology (K.J.B.), John
Curtin School of Medical Research, Australian National University,
Canberra, Australia
Through direct synthetic efforts, we discovered a small molecule that
is a nanomolar inhibitor of the human fibroblast growth factor-1
receptor (FGFR) tyrosine kinase. PD 166866, a member of a new
structural class of tyrosine kinase inhibitors, the
6-aryl-pyrido[2,3-d]pyrimidines, was identified by
screening a compound library with assays that measure protein tyrosine
kinase activity. PD 166866 inhibited human full-length FGFR-1 tyrosine
kinase with an IC50 value of 52.4 ± 0.1 nM and was
further characterized as an ATP competitive inhibitor of the FGFR-1. In
contrast, PD 166866 had no effect on c-Src, platelet-derived growth
factor receptor-
, epidermal growth factor receptor or insulin
receptor tyrosine kinases or on mitogen-activated protein kinase,
protein kinase C and CDK4 at concentrations as high as 50 µM. PD 166866 was a potent inhibitor of basic fibroblast growth
factor (bFGF)-mediated receptor autophosphorylation in NIH 3T3 cells
expressing endogenous FGFR-1 and in L6 cells overexpressing the human
FGFR-1 tyrosine kinase, confirming a tyrosine kinase-mediated
mechanism. PD 166866 also inhibited bFGF-induced tyrosine
phosphorylation of the 44- and 42-kDa (ERK 1/2) mitogen-activated protein kinase isoforms in L6 cells, presumably via
inhibition of bFGF-stimulated FGFR-1 tyrosine kinase activation. PD
166866 did not inhibit platelet-derived growth factor, epidermal growth factor or insulin-stimulated receptor autophosphorylation in vascular smooth muscle, A431 or NIHIR cells, respectively, further supporting its specificity for the FGFR-1. In addition, daily exposure of PD
166866 to L6 cells at concentrations from 1 to 100 nM resulted in a
concentration-related inhibition of bFGF-stimulated cell growth for 8 consecutive days with an IC50 value of 24 nM. In contrast,
PD 166866 had little effect on platelet-derived growth factor-BB-stimulated growth of L6 cells or serum-stimulated vascular smooth muscle cell proliferation. Finally, PD 166866 was found to be a
potent inhibitor of microvessel outgrowth (angiogenesis) from cultured
artery fragments of human placenta. These results highlight the
discovery of PD 166866, a new nanomolar potent and selective small
molecule inhibitor of the FGFR-1 tyrosine kinase with potential use as
antiproliferative/antiangiogenic agent for such therapeutic targets as
tumor growth and neovascularization of atherosclerotic plaques.
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