Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain.
Angiogenesis, the sprouting of new blood vessels from pre-existing ones, is an essential physiological process in development, yet also plays a major role in the progression of human diseases such as diabetic retinopathy, atherosclerosis and cancer. The effects of the most potent angiogenic factors, vascular endothelial growth factor (VEGF), angiopoietin and fibroblast growth factor (FGF) are mediated through cell surface receptors that possess intrinsic protein tyrosine kinase activity. In this report, we describe a synthetic compound of the pyrido[2,3-d]pyrimidine class, designated PD 173074, that selectively inhibits the tyrosine kinase activities of the FGF and VEGF receptors. We show that systemic administration of PD 173074 in mice can effectively block angiogenesis induced by either FGF or VEGF with no apparent toxicity. To elucidate the determinants of selectivity, we have determined the crystal structure of PD 173074 in complex with the tyrosine kinase domain of FGF receptor 1 at 2.5 A resolution. A high degree of surface complementarity between PD 173074 and the hydrophobic, ATP-binding pocket of FGF receptor 1 underlies the potency and selectivity of this inhibitor. PD 173074 is thus a promising candidate for a therapeutic angiogenesis inhibitor to be used in the treatment of cancer and other diseases whose progression is dependent upon new blood vessel formation.
Department of Pharmacology, New York University Medical Center, New York, NY 10016, USA.
M
M
Mohammadi
S
S
Froum
J M
JM
Hamby
M C
MC
Schroeder
R L
RL
Panek
G H
GH
Lu
A V
AV
Eliseenkova
D
D
Green
J
J
Schlessinger
S R
SR
Hubbard
D016475:3T3 Cells; D000818:Animals; D002478:Cells, Cultured; D003315:Cornea / Q000098:blood supply; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor
D004791:Enzyme Inhibitors; C115711:PD 173074; D011743:Pyrimidines; D017468:Receptors, Fibroblast Growth Factor; D017978:Receptors, Growth Factor; C496349:Fgfr1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D040262:Receptors, Vascular Endothelial Growth Factor