Abstract
A new class of protein tyrosine kinase inhibitors was identified that is based on an oxindole core (indolinones). Two compounds from this class inhibited the kinase activity of fibroblast growth factor receptor 1 (FGFR1) and showed differential specificity toward other receptor tyrosine kinases. Crystal structures of the tyrosine kinase domain of FGFR1 in complex with the two compounds were determined. The oxindole occupies the site in which the adenine of adenosine triphosphate binds, whereas the moieties that extend from the oxindole contact residues in the hinge region between the two kinase lobes. The more specific inhibitor of FGFR1 induces a conformational change in the nucleotide-binding loop. This structural information will facilitate the design of new inhibitors for use in the treatment of cancer and other diseases in which cell signaling by tyrosine kinases plays a crucial role in disease pathogenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Adenosine Triphosphate / metabolism
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Amino Acid Sequence
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Animals
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Crystallography, X-Ray
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / metabolism*
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Enzyme Inhibitors / pharmacology
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / metabolism
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Hydrogen Bonding
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Mice
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Models, Molecular
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Phosphorylation
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Phosphotyrosine / metabolism
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Piperazines / chemistry
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Piperazines / metabolism*
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Piperazines / pharmacology
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / chemistry*
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Protein-Tyrosine Kinases / metabolism
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Pyrroles / chemistry
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Pyrroles / metabolism*
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Pyrroles / pharmacology
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Receptor Protein-Tyrosine Kinases*
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Receptor, Fibroblast Growth Factor, Type 1
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Receptor, Insulin / antagonists & inhibitors
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Receptor, Insulin / metabolism
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Receptors, Fibroblast Growth Factor / antagonists & inhibitors
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Receptors, Fibroblast Growth Factor / chemistry*
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Receptors, Fibroblast Growth Factor / metabolism
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Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors
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Receptors, Platelet-Derived Growth Factor / metabolism
Substances
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Enzyme Inhibitors
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Piperazines
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Pyrroles
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Receptors, Fibroblast Growth Factor
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SU 4984
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SU 5402
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Phosphotyrosine
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Adenosine Triphosphate
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ErbB Receptors
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Fgfr1 protein, mouse
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Protein-Tyrosine Kinases
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Receptor Protein-Tyrosine Kinases
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Receptor, Fibroblast Growth Factor, Type 1
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Receptor, Insulin
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Receptors, Platelet-Derived Growth Factor