Explore the pharmacology of Cediranib

Cediranib is a potent inhibitor of VEGFR-2 and VEGFR-3 and reduces growth of a wide range of tumor models by targeting tumor vasculature. Cediranib has selectivity for VEGFR-2 against a wide range of kinases, including the PDGFR family members CSF-1R and Flt-3 in cellular phosphorylation assays. Here we explore the pharmacology of cediranib in more depth, examining its activity against VEGFR-1 in cells and the PDGFR family members c-Kit, PDGFR-α, and PDGFR-β in vitro and in vivo within a dose range of 0.75 to 6 mg/kg which has been routinely examined within preclinical tumor xenograft experiments.

Cediranib inhibited VEGF-A–stimulated VEGFR-1 activation in AG1-G1-Flt1 cells (IC50 = 1.2 nmol/L). VEGF-A induced greatest phosphorylation of VEGFR-1 at tyrosine residues Y1048 and Y1053, which 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 (IC50 = 1–3 nmol/L) and in a stem cell factor–induced proliferation assay (IC50 = 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 (IC50 = 12–32 nmol/L) and PDGF-BB–stimulated cellular proliferation (IC50 = 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 with significantly less activity than against the VEGF receptors, or c-Kit.

This work highlights the significant challenge to accurately describe the relative activity of an ATP-competitive kinase inhibitor potent against more than one kinase. This requires consideration of activity at the recombinant kinase level, within multiple cellular phosphorylation and proliferation assays, and then in vivo potency against the pertinent kinase in target tissues. These data are all required to fully interpret observations made in preclinical models. The in vivo pharmacodynamic data that show that across the dose range cediranib is primarily a VEGF signaling inhibitor with activity against c-Kit. That a significant drop-off in potency is observed between ligand-induced receptor phosphorylation and cellular proliferation for c-Kit, PDGFR-α, and PDGFR-β, but not for VEGFR-2, in endothelial cell assays, combined with the relative order of potency against these targets within a number of in vitro assays, suggests that cediranib is primarily a VEGFR inhibitor/ angiogenesis inhibitors.

Reference:

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