Abstract
Inhibition of the vascular endothelial growth factor (VEGF) signaling pathway has emerged as one of the most promising new approaches for cancer therapy. We describe herein the key steps starting from an initial screening hit leading to the discovery of pazopanib, N(4)-(2,3-dimethyl-2H-indazol-6-yl)-N(4)-methyl-N(2)-(4-methyl-3-sulfonamidophenyl)-2,4-pyrimidinediamine, a potent pan-VEGF receptor (VEGFR) inhibitor under clinical development for renal-cell cancer and other solid tumors.
MeSH terms
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Animals
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Cells, Cultured
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Crystallography, X-Ray
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Cytochrome P-450 Enzyme Inhibitors
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Cytochrome P-450 Enzyme System / metabolism
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Humans
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Indazoles
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism
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Mice
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Models, Molecular
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Molecular Structure
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Neoplasms / blood supply
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Neoplasms / drug therapy
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Neoplasms / enzymology
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Pyrimidines / chemistry*
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Pyrimidines / pharmacology*
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Pyrimidines / therapeutic use
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Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*
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Receptors, Vascular Endothelial Growth Factor / chemistry
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Receptors, Vascular Endothelial Growth Factor / metabolism
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Sulfonamides / chemistry*
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Sulfonamides / pharmacology*
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Sulfonamides / therapeutic use
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Xenograft Model Antitumor Assays
Substances
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Cytochrome P-450 Enzyme Inhibitors
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Indazoles
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Isoenzymes
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Protein Kinase Inhibitors
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Pyrimidines
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Sulfonamides
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pazopanib
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Cytochrome P-450 Enzyme System
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Receptors, Vascular Endothelial Growth Factor