FGFRs x VEGFR1 x VEGF-A x PDGFR x VEGFR2 x VEGFR3

更新于：2024-11-01

基本信息

关联

项与 FGFRs x VEGFR1 x VEGF-A x PDGFR x VEGFR2 x VEGFR3 相关的药物

CBT-005

靶点

FGFRs x PDGFR x VEGF-A x VEGFR1 x VEGFR2 x VEGFR3

作用机制

FGFRs拮抗剂 [+5]

在研机构

Cloudbreak Therapeutics LLC初创企业

原研机构

Cloudbreak Therapeutics LLC初创企业

在研适应症

湿性年龄相关性黄斑变性

非在研适应症

糖尿病性黄斑水肿

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 FGFRs x VEGFR1 x VEGF-A x PDGFR x VEGFR2 x VEGFR3 相关的临床结果

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100 项与 FGFRs x VEGFR1 x VEGF-A x PDGFR x VEGFR2 x VEGFR3 相关的转化医学

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0 项与 FGFRs x VEGFR1 x VEGF-A x PDGFR x VEGFR2 x VEGFR3 相关的专利（医药）

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项与 FGFRs x VEGFR1 x VEGF-A x PDGFR x VEGFR2 x VEGFR3 相关的文献（医药）

2011-05-01·Molecular Cancer Therapeutics2区 · 医学

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

2区 · 医学

Article

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

AbstractCediranib 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 (IC50 = 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 (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. 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. Mol Cancer Ther; 10(5); 861–73. ©2011 AACR.