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CP-547632 is a novel, potent vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for cancer therapy. Signaling through vascular endothelial growth factor (VEGF) receptors (VEGFRs) is a key pathway initiating endothelial cell proliferation and migration resulting in angiogenesis, a requirement for human tumor growth and metastasis. CP-547632 was identified as a potent inhibitor of the VEGFR-2 and basic fibroblast growth factor (FGF) kinases (IC(50) = 11 and 9 nM, respectively). It is selective relative to epidermal growth factor receptor, platelet-derived growth factor beta, and other related TKs. CP-547632 also inhibits VEGF-stimulated autophosphorylation of VEGFR-2 in a whole cell assay with an IC(50) value of 6 nM. After oral administration of CP-547632 to mice bearing NIH3T3/H-ras tumors, VEGFR-2 phosphorylation in tumors was inhibited in a dose-dependent fashion (EC(50) = 590 ng/ml). CP-547632 did not significantly affect the pharmacologic profiles of paclitaxel and carboplatin. CP-547632 potently inhibits both basic FGF and VEGF-induced angiogenesis in vivo. CP-547632 is a well-tolerated, orally-bioavailable inhibitor presently under clinical investigation for the treatment of human malignancies.
| Cell Experiment | |
|---|---|
| Cell lines | Porcine aortic endothelial cells |
| Preparation method | Cells were seeded at 1.6 × 105 cells/ml in 2-ml growth medium (Ham’s F-12 medium supplemented with 10% FBS, 50,000 units each penicillin and streptomycin, and 500 μg/ml gentamicin) per well in six-well plates. On day 2, the growth medium was replaced with serum-depleted medium (as above, but with 0.1% FBS and 0.1% BSA), and cells were incubated overnight. Immediately before compound addition, the medium was replaced with serum-depleted medium without BSA. Compounds were diluted in 100% DMSO, added to the cells at a final DMSO concentration of 0.25% v/v, and incubated at 37°C for 1 h. The cells were then stimulated with 500 ng/ml VEGF (Becton Dickinson, prepared in serum-depleted medium supplemented with 10 mm NaVO4) and incubated as above for an additional 8 min. The medium was removed and the cells washed once with PBS supplemented with 1 mm NaVO4, then lysed with 1 ml of immunoprecipitation assay buffer [10 mm Tris-HCl (pH 7.5), 50 mm NaCl, 25 mm EDTA, 1% NP40, 0.25% sodium deoxycholate, 2 mm NaVO4, and 1 EDTA-free complete protease inhibitor tablet per 25 ml]. Cell lysates were centrifuged at 14,000 rpm to pellet cellular debris, transferred to a new tube containing 4 μg anti-Flk-1 (Santa Cruz Biotechnology Laboratories; C20), and incubated with agitation overnight at 4°C. The antibody-protein complex was captured with protein A agarose beads (Santa Cruz Biotechnology Laboratories) for 30 min at 4°C and the protein boiled off in the presence of DTT. After electrophoresis and transfer to Immobilon-P membranes, the blots were probed with antibodies recognizing either the protein (monoclonal anti-Flk-1; Santa Cruz Biotechnology Laboratories; A3) or anti-PY-HRP. After incubation of the blot in enhanced chemiluminescence reagent (Amersham), bands were visualized on film or using the Lumi-ImagerF1 (Roche). |
| Concentrations | 0~10 μ M |
| Incubation time | 1 h |
| Animal Experiment | |
|---|---|
| Animal models | athymic mice bearing Colo-205, DLD-1; and MDA-MB-231 cells tumour xenograft |
| Formulation | 5% Gelucire |
| Dosages | 6.25–100 mg/kg qd. for 24 days |
| Administration | oral gavage |
| Molecular Weight | 532.4 |
| Formula | C20H24BrF2N5O3S |
| CAS Number | 252003-65-9 |
| Solubility (25°C) | DMSO |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Related VEGFR/PDGFR Products |
|---|
| Conbercept
Conbercept (KH902) is a monoclonal antibody targeting VEGFRA fused to the IGHG1 Fc fragment. Conbercept is produced by the fusion of the second C-LIKE of FLT1 and the third and fourth C-LIKE of KDR with IGHG1 Fc. |
| SU5208
SU5208 inhibits vascular endothelial growth factor receptor-2 (VEGFR2). |
| VEGFR-IN-1
VEGFR-IN-1 is a potent angiogenesis inhibitor with IC50s of 0.02, 0.18, 0.24 7.3, and 7 µM for KDR, Flt-1, c-Kit, EGF-R, and c-Src, respectively. |
| (Z)-Orantinib
(Z)-Orantinib ((Z)-SU6668) is a potent, selective, orally active and ATP competitive inhibitor of Flk‐1/KDR, PDGFRβ, and FGFR1, with IC50s of 2.1, 0.008, and 1.2 µM, respectively. |
| (Rac)-SAR131675
(Rac)-SAR131675 is the racemate of SAR131675. |
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