title: Assessing the activity of cediranib, a VEGFR-2/3 tyrosine kinase inhibitor, against VEGFR-1 and members of the structurally related PDGFR family.
abstract: Cediranib is a potent inhibitor of the VEGF receptor (VEGFR)-2 and VEGFR-3 tyrosine kinases. This study assessed the activity of cediranib against the VEGFR-1 tyrosine kinase and the platelet-derived growth factor receptor (PDGFR)-associated kinases c-Kit, PDGFR-α, and PDGFR-β. Cediranib inhibited VEGF-A-stimulated VEGFR-1 activation in AG1-G1-Flt1 cells (IC(50) = 1.2 nmol/L). VEGF-A induced greatest phosphorylation of VEGFR-1 at tyrosine residues Y1048 and Y1053; this was reversed by cediranib. Potency against VEGFR-1 was comparable with that previously observed versus VEGFR-2 and VEGFR-3. Cediranib also showed significant activity against wild-type c-Kit in cellular phosphorylation assays (IC(50) = 1-3 nmol/L) and in a stem cell factor-induced proliferation assay (IC(50) = 13 nmol/L). Furthermore, phosphorylation of wild-type c-Kit in NCI-H526 tumor xenografts was reduced markedly following oral administration of cediranib (≥1.5 mg/kg/d) to tumor-bearing nude mice. The activity of cediranib against PDGFR-β and PDGFR-α was studied in tumor cell lines, vascular smooth muscle cells (VSMC), and a fibroblast line using PDGF-AA and PDGF-BB ligands. Both receptor phosphorylation (IC(50) = 12-32 nmol/L) and PDGF-BB-stimulated cellular proliferation (IC(50) = 32 nmol/L in human VSMCs; 64 nmol/L in osteosarcoma cells) were inhibited. In vivo, ligand-induced PDGFR-β phosphorylation in murine lung tissue was inhibited by 55% following treatment with cediranib at 6 mg/kg but not at 3 mg/kg or less. In contrast, in C6 rat glial tumor xenografts in mice, ligand-induced phosphorylation of both PDGFR-α and PDGFR-β was reduced by 46% to 61% with 0.75 mg/kg cediranib. Additional selectivity was showed versus Flt-3, CSF-1R, EGFR, FGFR1, and FGFR4. Collectively, these data indicate that cediranib is a potent pan-VEGFR kinase inhibitor with similar activity against c-Kit but is significantly less potent than PDGFR-α and PDGFR-β.
authors: Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Sandra R
authors: SR
authors: Brave
authors: Kirsty
authors: K
authors: Ratcliffe
authors: Zena
authors: Z
authors: Wilson
authors: Neil H
authors: NH
authors: James
authors: Sue
authors: S
authors: Ashton
authors: Anna
authors: A
authors: Wainwright
authors: Jane
authors: J
authors: Kendrew
authors: Philippa
authors: P
authors: Dudley
authors: Nicola
authors: N
authors: Broadbent
authors: Graham
authors: G
authors: Sproat
authors: Sian
authors: S
authors: Taylor
authors: Claire
authors: C
authors: Barnes
authors: Jeffrey C
authors: JC
authors: Silva
authors: Charles L
authors: CL
authors: Farnsworth
authors: Laurent
authors: L
authors: Hennequin
authors: Donald J
authors: DJ
authors: Ogilvie
authors: Juliane M
authors: JM
authors: Jürgensmeier
authors: Masabumi
authors: M
authors: Shibuya
authors: Stephen R
authors: SR
authors: Wedge
authors: Simon T
authors: ST
authors: Barry
mesh_terms: D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008168:Lung / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D019089:Stem Cell Factor / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors; D007211:Indoles
chemical_list: D008024:Ligands; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit; D011799:Quinazolines; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D019089:Stem Cell Factor; D051941:fms-Like Tyrosine Kinase 3; C497970:FLT3 protein, human; C500926:cediranib; D007211:Indoles