Motesanib Diphosphate (AMG-706)

Catalog No.S1032
5 5 3 Product Citations

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, ~10-fold more selective for VEGFR than PDGFR and Ret. Phase 3.

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Motesanib Diphosphate (AMG-706) Chemical Structure

Motesanib Diphosphate (AMG-706) Chemical Structure
Molecular Weight: 569.44

Validation & Quality Control

Customer Reviews(2)

Quality Control & MSDS

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  • Research Area
  • Inhibition Profile
  • Motesanib Diphosphate (AMG-706) Mechanism

Product Description

Biological Activity

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, ~10-fold more selective for VEGFR than PDGFR and Ret. Phase 3.
Targets VEGFR1 [1] VEGFR2 [1] VEGFR2/Flk1 [1] VEGFR3 [1] Kit [1]

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IC50 2 nM 3 nM 6 nM 6 nM 8 nM
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 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. [1] Administration of Motesanib Diphosphate in combination with radiation displays significant anti-tumor activity in head and neck squamous cell carcinoma (HNSCC) xenograft models. [2] 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. [3]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

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.

Cell Assay: [1]

Cell lines A431, MO7e, HUVEC and NHDF cells
Concentrations Dissolved in DMSO, final concentrations ~25 μM
Incubation Time 2 hours
Method Cells are preincubated for 2 hours with different concentrations of Motesanib Diphosphate, 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 Study: [1]

Animal Models Female Sprague-Dawley rats with induced corneal angiogenesis, and female CD-1 nu/nu mice injected s.c. with A431 cells
Formulation Formulated as a suspension in Ora-Plus vehicle adjusted to pH 2.0
Dosages ~100 mg/kg
Administration Orally administered twice daily or once daily
Solubility Saline, 30 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
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.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Polverino A, et al. Cancer Res, 2006, 66(17), 8715-8721.

[2] Kruser TJ, et al. Clin Cancer Res, 2010, 16(14), 3639-3647.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-12-20)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01386866 Completed Advanced Solid Tumors Amgen May 2009 Phase 1
NCT01386866 Completed Advanced Solid Tumors Amgen May 2009 Phase 1
NCT00427349 Active, not recruiting Gastrointestinal Carcinoid Tumor|Islet Cell Tumor|Neoplastic Syndrome Eastern Cooperative Oncology Group|National Cancer Instit  ...more Eastern Cooperative Oncology Group|National Cancer Institute (NCI) September 2008 Phase 2
NCT00427349 Active, not recruiting Gastrointestinal Carcinoid Tumor|Islet Cell Tumor|Neoplastic Syndrome Eastern Cooperative Oncology Group|National Cancer Instit  ...more Eastern Cooperative Oncology Group|National Cancer Institute (NCI) September 2008 Phase 2
NCT00574951 Active, not recruiting Fallopian Tube Cancer|Ovarian Cancer|Primary Peritoneal Cavity Cancer Gynecologic Oncology Group|National Cancer Institute (NCI) December 2007 Phase 2

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Chemical Information

Download Motesanib Diphosphate (AMG-706) SDF
Molecular Weight (MW) 569.44
Formula

C22H23N5O.2H3PO4

CAS No. 857876-30-3
Storage 3 years -20℃Powder
6 months-80℃in solvent (DMSO, water, etc.)
Synonyms
Solubility (25°C) * In vitro DMSO 100 mg/mL heating (175.61 mM)
Water 19 mg/mL heating (33.36 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo Saline 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 3-Pyridinecarboxamide, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-, phosphate (1:2)

Research Area

Customer Reviews (2)


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Rating
Source Cardiovasc Res 2011 91, 402-11. Motesanib Diphosphate (AMG-706) purchased from Selleck
Method FACS analysis
Cell Lines cardiac stem cell (CSC)
Concentrations 2 nM
Incubation Time 30 min
Results All VEGFR inhibitors (incuding AMG-706, inhibited VEGFCM-mediated CSC migration.

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Rating
Source Cardiovasc Res 2011 91, 402-11. Motesanib Diphosphate (AMG-706) purchased from Selleck
Method flow cytometry/CSC migration assay
Cell Lines CSCs
Concentrations 2 nM
Incubation Time 30 min
Results the migratory response of CSC to VEGFCM was increased two-fold compared with control. AMG-706 and other VEGFR inhibitors inhibited VEGFCM-mediated CSC migration, although VEGFR1 and VEGFR3 inhibitors had a greater effect than VEGFR2 inhibitor, consistent with their effect on CXCR4 expression.

Product Citations (3)

Tech Support & FAQs

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