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 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 models||athymic mice bearing Colo-205, DLD-1; and MDA-MB-231 cells tumour xenograft|
|Dosages||6.25–100 mg/kg qd. for 24 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
A phase I/randomized phase II, non-comparative, multicenter, open label trial of CP-547,632 in combination with paclitaxel and carboplatin or paclitaxel and carboplatin alone as first-line treatment for advanced non-small cell lung cancer (NSCLC).
Cohen RB, et al. Cancer Chemother Pharmacol. 2007 Jun;60(1):81-9. PMID: 17031646.
Pharmacological characterization of CP-547,632, a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for cancer therapy.
Beebe JS, et al. Cancer Res. 2003 Nov 1;63(21):7301-9. PMID: 14612527.
|Related VEGFR/PDGFR Products|
Avapritinib (BLU-285) is a small molecule kinase inhibitor that potently inhibits PDGFRα D842V mutant activity in vitro (IC50 = 0.5 nM) and PDGFRα D842V autophosphorylation in the cellular setting (IC50 = 30 nM); also a potent inhibitor of the analogous KIT mutation, D816V in KIT Exon 17 (IC50 = 0.5 nM).
|Nintedanib Ethanesulfonate Salt
BIBF 1120 esylate is a potent triple angiokinase inhibitor for VEGFR1/2/3, FGFR1/2/3 and PDGFRα/β with IC50s of 34 nM/13 nM/13 nM, 69 nM/37 nM/108 nM and 59 nM/65 nM, respectively.
Regorafenib (BAY 73-4506) is a multi-target inhibitor for VEGFR1, VEGFR2, VEGFR3, PDGFRβ, Kit, RET and Raf-1 with IC50 of 13 nM/4.2 nM/46 nM, 22 nM, 7 nM, 1.5 nM and 2.5 nM, respectively.
|Pazopanib HCl (GW786034 )
Pazopanib HCl (GW786034 HCl) is a novel multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFR, FGFR, c-Kit and c-Fms with IC50 of 10 nM, 30 nM, 47 nM, 84 nM, 74 nM, 140 nM and 146 nM in cell-free assays, respectively.
|Dovitinib (TKI-258) Dilactic Acid
Dovitinib Dilactic acid (TKI258 Dilactic acid) is the Dilactic acid of Dovitinib, which is a multitargeted RTK inhibitor, mostly for class III (FLT3/c-Kit) with IC50 of 1 nM/2 nM.
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