Sunitinib: a VEGF and PDGF receptor protein kinase and angiogenesis inhibitor.
Sunitinib (SU-11248, Sutent) inhibits at least eight receptor protein-tyrosine kinases including vascular endothelial growth factor receptors 1-3 (VEGFR1-VEGFR3), platelet-derived growth factor receptors (PDGFRalpha and PDGFRbeta), stem cell factor receptor (Kit), Flt-3, and colony-stimulating factor-1 receptor (CSF-1R). VEGFR1 and VEGFR2 play key roles in vasculogenesis and angiogenesis. PDGFRbeta, which is found in pericytes that surround capillary endothelial cells, plays a pivotal role in stabilizing the vascular endothelium. Sunitinib inhibits angiogenesis by diminishing signaling through VEGFR1, VEGFR2, and PDGFRbeta. Renal cell cancers that have metastasized, or spread from the primary tumor, exhibit extensive vascularity, and sunitinib is approved for the treatment of these neoplasms. Activating Kit mutations occur in about 85% of gastrointestinal stromal tumors and activating PDGFRalpha mutations occur in about 5% of these tumors. Sunitinib is approved for the treatment of those tumors that are resistant to imatinib (STI-571, Gleevec), another Kit and PDGFRalpha protein-tyrosine kinase inhibitor. Both sunitinib and imatinib bind reversibly to the ATP binding site of their target kinases and thereby inhibit their catalytic activity.
Roskoski
Robert
R
Blue Ridge Institute for Medical Research, Horse Shoe, NC 28742, USA. rrj@brimr.org
D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D001682:Biological Availability; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D011758:Pyrroles / Q000493:pharmacokinetics / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D000077210:Sunitinib; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D017479:Receptors, Platelet-Derived Growth Factor; D000077210:Sunitinib