Motesanib Diphosphate?is a diphosphate form of motesanib. It is a potent ATP-competitive inhibitor of VEGFR1/2/3 with IC50 of 2 nM/3 nM/6 nM, respectively [1].
Vascular endothelial growth factor (VEGF) is an important signaling protein involved in both vasculogenesis (the formation of the circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature). Motesanib (AMG 706) is an orally administered small molecule belonging to angiokinase inhibitor class which acts as an antagonist of VEGF receptors, platelet-derived growth factor receptors, and stem cell factor receptors.
In vitro: Motesanib diphosphate has broad activity against the human VEGFR family, and displays >1000 selectivity against EGFR, Src, and p38 kinase. Motesanib Diphosphate significantly inhibits VEGF-induced cellular proliferation of HUVECs with an IC50 of 10 nM, while displaying little effect at bFGF-induced proliferation with an IC50 of >3,000 nM. Motesanib Diphosphate also potently inhibits PDGF-induced proliferation and SCF-induced c-kit phosphorylation with IC50 of 207 nM and 37 nM, respectively, but not effective against the EGF-induced EGFR phosphorylation and cell viability of A431 cells [1]. Althouth displaying little antiproliferative activity on cell growth of HUVECs alone, Motesanib diphosphate treatment significantly sensitizes the cells to fractionated radiation [2].?
In vivo: Oral administration of AMG 706 potently inhibited VEGF-induced angiogenesis in the rat corneal model and induced regression of established A431 xenografts. AMG 706 was well tolerated and had no significant effects o AMG 706n body weight or on the general health of the animals. Histologic analysis of tumor xenografts from AMG 706–treated animals revealed an increase in endothelial apoptosis and a reduction in blood vessel area that preceded an increase in tumor cell apoptosis. In summary, AMG 706 is an orally bioavailable, well-tolerated multikinase inhibitor that is presently under clinical investigation for the treatment of human malignancies [1].?
Clinical trial: Motesanib was originally investigated for effectiveness against advanced nonsquamous non-small-cell lung cancer (NSCLC), with Phase II trials indicating an effectiveness comparable to bevacizumab when they were both used in combination with paclitaxel/carboplatin. However a later and more detailed Phase III trial failed to show any benefit for the treatment of NSCLC. A second Phase III trial was started in 2012, which focused on patients from Asian backgrounds (performed on the bases of subgroup analysis) however this also failed to meet its primary endpoint. The drug has undergone a Phase II evaluation as first-line therapy for breast cancer however this study found no evidence to support further investigation. Phase II testing against persistent or recurrent ovarian, fallopian tube and primary peritoneal carcinomas was also unsuccessful. There have also been 2 separate Phase II clinical trials for thyroid cancer which have both shown promising results (http://en.wikipedia.org/wiki/Motesanib).?
参考文献:
[1] Polverino A, Coxon A, Starnes C, et al. AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res. 2006;66(17):8715-21.
[2] Kruser TJ1 Wheeler DL, Armstrong EA, Iida M, Kozak KR, van der Kogel AJ, Bussink J, Coxon A, Polverino A, Harari PM. Augmentation of radiation response by motesanib, a multikinase inhibitor that targets vascular endothelial growth factor receptors. Clin Cancer Res. 2010;16(14):3639-47.
Kinase experiment: | Optimal enzyme, ATP, and substrate (gastrin peptide) concentrations are established for each enzyme using homogeneous time-resolved fluorescence (HTRF) assays. Motesanib is tested in a 10-point dose-response curve for each enzyme using an ATP concentration of two-thirds Km for each. Most assays consist of enzyme mixed with kinase reaction buffer [20 mM Tris-HCl (pH 7.5), 10 mM MgCl2, 5 mM MnCl2, 100 mM NaCl, 1.5 mM EGTA]. A final concentration of 1 mM DTT, 0.2 mM NaVO4, and 20 μg/mL BSA is added before each assay. For all assays, 5.75 mg/mL streptavidin-allophycocyanin and 0.1125 nM Eu-PT66 are added immediately before the HTRF reaction. Plates are incubated for 30 minutes at room temperature and read on a Discovery instrument. IC50 values are calculated using the Levenberg-Marquardt algorithm into a four-parameter logistic equation. |
Cell experiment: | Cells are preincubated for 2 hours with different concentrations of Motesanib, and exposed with 50 ng/mL VEGF or 20 ng/mL bFGF for an additional 72 hours. Cells are washed twice with DPBS, and plates are frozen at -70°C for 24 hours. Proliferation is assessed by the addition of CyQuant dye, and plates are read on a Victor 1420 workstation. IC50 data are calculated using the Levenberg-Marquardt algorithm into a four-parameter logistic equatio. |
Animal experiment: | A431 cells are cultured in DMEM (low glucose) with 10% FBS and penicillin/streptomycin/glutamine. Cells are harvested by trypsinization, washed, and adjusted to a concentration of 5×107/mL in serum-free medium. Animals are challenged s.c. with 1×107 cells in 0.2 mL over the left flank. Approximately 10 days thereafter, mice are randomized based on initial tumor volume measurements and treated with either vehicle (Ora-Plus) or Motesanib. Tumor volumes and body weights are recorded twice weekly and/or on the day of sacrifice. Tumor volume is measured with a Pro-Max electronic digital caliper and calculated using the formula length (mm)×width (mm)×height (mm) and expressed in mm3. Data are expressed as mean±SE. Repeated measures ANOVA followed by Scheffe post hoc testing for multiple comparisons is used to evaluate the statistical significance of observed differences[1]. |
参考文献: [1]. Polverino A, et al. AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res. 2006 Sep 1;66(17):8715-21. | |
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