CAS 857876-30-3|Motesanib Diphosphate (AMG-706)
Introduction：Basic information about CAS 857876-30-3|Motesanib Diphosphate (AMG-706), including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
| Common Name | Motesanib Diphosphate (AMG-706) | ||
|---|---|---|---|
| CAS Number | 857876-30-3 | Molecular Weight | 569.441 |
| Density | / | Boiling Point | 858.7ºC at 760 mmHg |
| Molecular Formula | C22H29N5O9P2 | Melting Point | / |
| MSDS | / | Flash Point | 473.1ºC |
Names
| Name | N-(3,3-dimethyl-1,2-dihydroindol-6-yl)-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide,phosphoric acid |
|---|---|
| Synonym | More Synonyms |
Motesanib Diphosphate (AMG-706) BiologicalActivity
| Description | Motesanib Diphosphate is a potent ATP-competitive inhibitor of VEGFR1/2/3 with IC50s of 2 nM/3 nM/6 nM, respectively, and has similar activity against Kit, and is approximately 10-fold more selective for VEGFR than PDGFR and Ret. |
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| Related Catalog | Signaling Pathways >>Protein Tyrosine Kinase/RTK >>c-KitResearch Areas >>Cancer |
| Target | VEGFR1:2 nM (IC50) VEGFR2:3 nM (IC50) VEGFR3:6 nM (IC50) |
| In Vitro | Motesanib has broad activity against the human VEGFR family, and displays over 1000-fold selectivity against EGFR, Src, and p38 kinase. Motesanib 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 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]. Although displaying little antiproliferative activity on cell growth of HUVECs alone, Motesanib treatment significantly sensitizes the cells to fractionated radiation[2]. |
| In Vivo | Motesanib (100 mg/kg) significantly inhibits VEGF-induced vascular permeability in a time-dependent manner. Oral administration of Motesanib 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 induces a dose-dependent tumor regression of established A431 xenografts by selectively targeting neovascularization in tumor cells[1]. Motesanib in combination with radiation displays significant anti-tumor activity in head and neck squamous cell carcinoma (HNSCC) xenograft models[2]. Motesanib 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[3]. |
| Kinase Assay | 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 Assay | 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 Admin | 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]. |
| References | [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. [2]. Kruser TJ, et al. Augmentation of radiation response by motesanib, a multikinase inhibitor that targets vascular endothelial growth factor receptors. Clin Cancer Res, 2010, 16(14), 3639-3647. [3]. Coxon A, et al. Broad antitumor activity in breast cancer xenografts by motesanib, a highly selective, oral inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and Kit receptors. Clin Cancer Res, 2009, 15(1), 110-118. |
Chemical & Physical Properties
| Boiling Point | 858.7ºC at 760 mmHg |
|---|---|
| Molecular Formula | C22H29N5O9P2 |
| Molecular Weight | 569.441 |
| Flash Point | 473.1ºC |
| Exact Mass | 569.144043 |
| PSA | 257.57000 |
| LogP | 2.78190 |
| InChIKey | ONDPWWDPQDCQNJ-UHFFFAOYSA-N |
| SMILES | CC1(C)CNc2cc(NC(=O)c3cccnc3NCc3ccncc3)ccc21.O=P(O)(O)O.O=P(O)(O)O |
| Storage condition | -20°C |
Synonyms
| AMG-706. Motesanib Diphosphate |
| Motesanib Diphosphate (AMG-706) |
| S1032_Selleck |
| N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]nicotinamide phosphate (1:2) |
| AMG-706 |
| Motesanib Diphosphate |
| Motesanib diphosphate (USAN) |
| Motesanib (Diphosphate) |
| 3-Pyridinecarboxamide, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-, phosphate (1:2) |
| UNII-T6Q3060U91 |
