Motesanib Diphosphate (AMG-706)
For research use only.
CAS No. 857876-30-3
Motesanib Diphosphate (AMG-706) is a potent ATP-competitive inhibitor of VEGFR1/2/3 with IC50 of 2 nM/3 nM/6 nM, respectively; similar activity against Kit (c-Kit), ~10-fold more selective for VEGFR than PDGFR and Ret. Phase 3.
Selleck's Motesanib Diphosphate (AMG-706) has been cited by 10 publications
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Immunofluorescence staining of choroidal neovascularization (CNV) lesions 14 days after laser photocoagulation. Choroidal flat mounts were fluorescently labeled with F-actin-specific marker phalloidin (green channel), endothelial cell marker CD34 (red channel), and nuclear marker DAPI (blue channel). CNV lesions in topical vehicle-treated eye (A, C, E and G) and topical motesanib-treated eye (B, D, F and H). The scale bar represents 100 um.
J Ocul Pharmacol Ther 2014 10.1089/jop.2014.0023. Motesanib Diphosphate (AMG-706) purchased from Selleck.
(C, D, E)VEGFCM stimulated CXCR4 expression in CSC 24 h after VEGFCM treatment. CSC were untreated (Control, C), or treated with VEGFMSC-conditioned medium (VEGFCM, D) or VEGFCM and VEGFR1 inhibitor AMG(E) followed by flow cytometry. AMG inhibited the expression of VEGFCM-induced CXCR4. (F) Quantitative analysis of CXCR4 expression by flow cytometry. CSC were treated with CtrlCM or VEGFCM with or without VEGFR specific inhibitors for VEGFR1 (AMG), VEGFR2 (VEGFR2-I), and VEGFR3 (MAZ).*P , 0.05 vs. control, AMG, VEGFR2-I. and MAZ; #P , 0.05 vs. AMG and MAZ (n = 5). (G) CtrlCM promoted CSC migration. *P , 0.05 vs. CtrlCM; OP , 0.01 vs. CtrlCM; &P , 0.05 vs. CtrlCM+AMG and <sup>Ctrl</sup>CM+MAZ (n ?15); @P , 0.01 vs. CtrlCM; PP , 0.01 vs. CtrlCM; $P , 0.05 vs. CtrlCM+AMG and CtrlCM+MAZ. Note: CtrlCM= CtrlMSC< mesenchymal stem cells>-conditioned medium
Cardiovasc Res 2011 91, 402-11. Motesanib Diphosphate (AMG-706) purchased from Selleck.
(F ) Quantitative analysis of CXCR4 expression by flow cytometry. CSC were treated with CtrlCM or VEGFCM with or without VEGFR specific inhibitors for VEGFR1 (AMG), VEGFR2 (VEGFR2-I), and VEGFR3 (MAZ). *P<0.05 vs. control, AMG, VEGFR2-I. and MAZ; #P<0.05 vs. AMG and MAZ ( n=5). ( G ) VEGFCM promoted CSC migration. *P<0.05 vs. CtrlCM; ▲P<0.01 vs. CtrlCM; &P<0.05 vs. CtrlCM+ AMG and CtrlCM+ MAZ ( n=15); @P <0.01 vs. CtrlCM; P <0.01 vs. CtrlCM; $P <0.05 vs. VEGFCM+ AMG and VEGFCM+ MAZ.
Cardiovasc Res 2011 91, 402-11. Motesanib Diphosphate (AMG-706) purchased from Selleck.
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Choose Selective VEGFR Inhibitors
|Description||Motesanib Diphosphate (AMG-706) is a potent ATP-competitive inhibitor of VEGFR1/2/3 with IC50 of 2 nM/3 nM/6 nM, respectively; similar activity against Kit (c-Kit), ~10-fold more selective for VEGFR than PDGFR and Ret. Phase 3.|
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.  Althouth displaying little antiproliferative activity on cell growth of HUVECs alone, Motesanib Diphosphate treatment significantly sensitizes the cells to fractionated radiation. 
|In vivo||Administration of Motesanib Diphosphate at 100 mg/kg significantly inhibits VEGF-induced vascular permeability in a time-dependent manner. Oral administration of Motesanib Diphosphate twice daily or once daily potently inhibits, in a dose-dependent manner, VEGF-induced angiogenesis using the rat corneal model with ED50 of 2.1 mg/kg and 4.9 mg/kg, respectively. Motesanib Diphosphate induces a dose-dependent tumor regression of established A431 xenografts by selectively targeting neovascularization in tumor cells.  Administration of Motesanib Diphosphate in combination with radiation displays significant anti-tumor activity in head and neck squamous cell carcinoma (HNSCC) xenograft models.  Motesanib Diphosphate treatment also induces significant dose-dependent reductions in tumor growth and blood vessel density of MCF-7, MDA-MB-231, or Cal-51 xenografts, which can be markedly enhanced when combined with docetaxel or tamoxifen. |
In vitro kinase assays:Optimal enzyme, ATP, and substrate (gastrin peptide) concentrations are established for each enzyme using homogeneous time-resolved fluorescence (HTRF) assays. Motesanib Diphosphate 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.
|In vitro||DMSO||100 mg/mL warmed (175.61 mM)|
|Water||19 mg/mL warmed (33.36 mM)|
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Clinical Trial Information
|NCT Number||Recruitment||interventions||Conditions||Sponsor/Collaborators||Start Date||Phases|
|NCT01386866||Completed||Drug: AMG 706||Advanced Solid Tumors||Amgen||May 2009||Phase 1|
|NCT00448786||Completed||Drug: AMG 706||Solid Tumors||Amgen||February 2007||Phase 1|
|NCT00322400||Completed||Drug: Docetaxel|Drug: Paclitaxel|Drug: AMG 706||Locally Recurrent and Metastatic Breast Cancer||Amgen||March 2006||Phase 1|
|NCT01235416||Completed||Drug: AMG 706||Histologically or Cytologically Documented Solid Tumors||Amgen||September 2005||Phase 1|
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