Motesanib Diphosphate (AMG-706)

Catalog No.S1032 Batch:S103202

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Technical Data

Formula

C22H23N5O.2H3PO4

Molecular Weight 569.44 CAS No. 857876-30-3
Solubility (25°C)* In vitro DMSO 100 mg/mL (175.61 mM)
Water 19 mg/mL (33.36 mM)
Ethanol Insoluble
* <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.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

Preparing Stock Solutions

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

Protocol (from 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

  • Dosages

    ~100 mg/kg

  • Administration

    Orally administered twice daily or once daily

Customer Product Validation

Data from [Data independently produced by J Ocul Pharmacol Ther, 2014, 10.1089/jop.2014.0023]

Data from [Cardiovasc Res, 2011, 91, 402-11]

Data from [Cardiovasc Res, 2011, 91, 402-11]

Selleck's Motesanib Diphosphate (AMG-706) has been cited by 12 publications

Anosmin-1-Like Effect of UMODL1/Olfactorin on the Chemomigration of Mouse GnRH Neurons and Zebrafish Olfactory Axons Development [ Front Cell Dev Biol, 2022, 10:836179] PubMed: 35223856
Preclinical Evaluation of Ixabepilone in Combination with VEGF Receptor and PARP Inhibitors in Taxane-Sensitive and Taxane-Resistant MDA-MB-231 Breast Cancer Cells [ J Pharm Sci, 2022, 111(8):2180-2190] PubMed: 35700798
Extension of the Mechanistic Tissue Distribution Model of Rodgers and Rowland by Systematic Incorporation of Lysosomal Trapping: Impact on Unbound Partition Coefficient and Volume of Distribution Predictions in the Rat [ Drug Metab Dispos, 2021, 49(1):53-61] PubMed: 33148688
Cardiac Reprogramming Factors Synergistically Activate Genome-wide Cardiogenic Stage-Specific Enhancers [ Cell Stem Cell, 2019, 25(1):69-86] PubMed: 31080136
Targeting the Kaposi Sarcoma Herpesvirus ORF 21 tyrosine kinase and viral lytic reactivation by tyrosine kinase inhibitors approved for clinical use. [ J Virol, 2019, 10.1128/JVI.01791-19] PubMed: 31826996
[ Cancer Res, 2016, ] PubMed: 27488524
Dual inhibition of EGFR and MET induces synthetic lethality in triple-negative breast cancer cells through downregulation of ribosomal protein S6 [ Int J Oncol, 2015, 47(1):122-32] PubMed: 25955731
VEGF/SDF-1 promotes cardiac stem cell mobilization and myocardial repair in the infarcted heart. [Tang JM, et al. Int J Cardiol, 2015, 183C:221-231] PubMed: 25679991
Antiangiogenic Effects of Topically Administered Multiple Kinase Inhibitor, Motesanib (AMG 706), on Experimental Choroidal Neovascularization in Mice [Rho CR, et al. J Ocul Pharmacol Ther, 2015, 31(1):25-31]
Bioluminescent cell-based NAD(P)/NAD(P)H assays for rapid dinucleotide measurement and inhibitor screening [ Assay Drug Dev Technol, 2014, 12(9-10):514-26] PubMed: 25506801

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SHIPPING AND STORAGE
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