Assessing the Activity of Cediranib, a VEGFR-2/3 Tyrosine Kinase Inhibitor, against VEGFR-1 and Members of the Structurally Related PDGFR Family

作者：Brave Sandra R; Ratcliffe Kirsty; Wilson Zena; James Neil H; Ashton Sue; Wainwright Anna; Kendrew Jane; Dudley Philippa; Broadbent Nicola; Sproat Graham; Taylor Sian; Barnes Claire; Silva Jeffrey C; Farnsworth Charles L; Hennequin Laurent; Ogilvie Donald J; Juergensmeier Juliane M; Shibuya Masabumi; Wedge Stephen R; Barry Simon T^*

来源：Molecular Cancer Therapeutics, 2011, 10(5): 861-873.

DOI：10.1158/1535-7163.MCT-10-0976

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-alpha, and PDGFR-beta. 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 wildtype 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-beta and PDGFR-alpha 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-beta 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-alpha and PDGFR-beta 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-alpha and PDGFR-beta. Mol Cancer Ther; 10(5); 861-73.

• 出版日期2011-5