Motesanib Diphosphate (AMG-706)

Alias: AMG-706; Motesanib Diphosphate; AMG 706; AMG706; motesanib phosphate;
Cat No.:V0531 Purity: ≥98%
Motesanib, the diphosphate salt of Motesanib (formerly AMG706) is an ATP-competitive and orally bioavailable inhibitor of vascular endothelial growth factor (VEGFR1/2/3) with potential antitumor activity.
Motesanib Diphosphate (AMG-706) Chemical Structure CAS No.: 857876-30-3
Product category: VEGFR
This product is for research use only, not for human use. We do not sell to patients.
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Other Forms of Motesanib Diphosphate (AMG-706):

  • Motesanib
Official Supplier of:
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

Motesanib, the diphosphate salt of Motesanib (formerly AMG706) is an ATP-competitive and orally bioavailable inhibitor of vascular endothelial growth factor (VEGFR1/2/3) with potential antitumor activity. Its IC50s are 2 nM, 3 nM, and 6 nM for VEGFR1/2/3 inhibition, respectively.

Biological Activity I Assay Protocols (From Reference)
Targets
VEGFR1 (IC50 = 2 nM); VEGFR2 (IC50 = 3 nM); VEGFR2/Flk1 (IC50 = 6 nM); VEGFR3 (IC50 = 6 nM); Kit (IC50 = 8 nM)
ln Vitro

Motesanib Diphosphate (AMG 706 Diphosphate) exhibits over 1000-fold selectivity against EGFR, Src, and p38 kinase, and broad activity against the human VEGFR family.With an IC50 of 10 nM, motesanib diphosphate (AMG 706 Diphosphate) dramatically suppresses HUVECs' VEGF-induced cellular proliferation, but has no effect on bFGF-induced proliferation (IC50 of >3,000 nM). With IC50 values of 207 nM and 37 nM, respectively, motesanib diphosphate (AMG 706 Diphosphate) also effectively suppresses PDGF-induced proliferation and SCF-induced c-kit phosphorylation, but it is ineffective against EGF-induced EGFR phosphorylation and A431 cell viability[1]. Despite having minimal effect on HUVECs' ability to proliferate, Motesanib Diphosphate (AMG 706 Diphosphate) treatment greatly increases the cells' sensitivity to fractionated radiation[2].

ln Vivo
Motesanib Diphosphate (AMG 706 Diphosphate) at a dose of 100 mg/kg substantially reduces VEGF-induced vascular permeability in a time-dependent manner. Using the rat corneal model, oral Motesanib administration twice daily or once daily potently inhibits VEGF-induced angiogenesis in a dose-dependent manner (ED50 of 2.1 mg/kg and 4.9 mg/kg, respectively). By specifically targeting neovascularization in tumor cells, motesanib diphosphate (AMG 706 Diphosphate) causes a dose-dependent tumor regression in established A431 xenografts[1]. Head and neck squamous cell carcinoma (HNSCC) xenograft models demonstrate notable anti-tumor activity when administered in conjunction with motesanib diphosphate (AMG 706 Diphosphate) and radiation[2]. In MCF-7, MDA-MB-231, or Cal-51 xenografts, motesanib diphosphate (AMG 706 Diphosphate) treatment also significantly reduces tumor growth and blood vessel density in a dose-dependent manner. These effects can be further amplified when combined with tamoxifen or docetaxel[3].
Enzyme Assay
Homogeneous time-resolved fluorescence (HTRF) assays are used to determine suitable enzyme, ATP, and substrate (gastrin peptide) concentrations for each enzyme. Using a two-thirds Km ATP concentration for each enzyme, motesanib is tested in a 10-point dose-response curve. An enzyme is combined with kinase reaction buffer (20 mM Tris-HCl (pH 7.5), 10 mM MgCl2, 5 mM MnCl2, 100 mM NaCl, 1.5 mM EGTA) in the majority of assays. Prior to each experiment, a final concentration of 20 μg/mL BSA, 0.2 mM NaVO4, and 1 mM DTT is added. The HTRF reaction is preceded in all assays by the addition of 0.1125 nM Eu-PT66 and 5.75 mg/mL streptavidin-allophycocyanin. Using a Discovery instrument, plates are read after 30 minutes of room temperature incubation. Levenberg-Marquardt algorithm is used to calculate IC50 values, which are then entered into a four-parameter logistic equation.
Cell Assay
After exposing the cells to either 50 ng/mL VEGF or 20 ng/mL bFGF for an extra 72 hours, the cells are preincubated for two hours at varying concentrations of motesanib. Plates are frozen for 24 hours at -70°C after cells are twice cleaned with DPBS. Plates are read using a Victor 1420 workstation, and proliferation is measured by adding CyQuant dye. The four-parameter logistic equation is derived from the IC50 data using the Levenberg-Marquardt algorithm.
Animal Protocol
DMEM (low glucose) supplemented with 10% FBS, penicillin, streptomycin, and glutamine is used to cultivate A431 cells. Trypsinization is used to harvest the cells, which are then cleaned and concentrated to 5×107/mL in serum-free medium. 1x107 cells in 0.2 mL are given to the animals s.c. over the left flank as a challenge. After about ten days, mice are treated with either vehicle (Ora-Plus) or motesanib, according to initial tumor volume measurements. Body weights and tumor volumes are measured twice a week, as well as on the day of sacrifice. Using a Pro-Max electronic digital caliper, the tumor volume is measured and expressed in millimeter-three (mm3) by calculating the formula length (mm)×width (mm)×height (mm). The data is presented as mean±SE. Repeated actions ANOVA is used to assess the statistical significance of observed differences, with Scheffe post hoc testing for multiple comparisons used afterward[1].
References

[1]. 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]. 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]. 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.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C22H29N5O9P2
Molecular Weight
569.44
Exact Mass
569.14405151
Elemental Analysis
C, 46.40; H, 5.13; N, 12.30; O, 25.29; P, 10.88
CAS #
857876-30-3
Appearance
Solid powder
SMILES
CC1(CNC2=C1C=CC(=C2)NC(=O)C3=C(N=CC=C3)NCC4=CC=NC=C4)C.OP(=O)(O)O.OP(=O)(O)O
InChi Key
ONDPWWDPQDCQNJ-UHFFFAOYSA-N
InChi Code
InChI=1S/C22H23N5O.2H3O4P/c1-22(2)14-26-19-12-16(5-6-18(19)22)27-21(28)17-4-3-9-24-20(17)25-13-15-7-10-23-11-8-15;2*1-5(2,3)4/h3-12,26H,13-14H2,1-2H3,(H,24,25)(H,27,28);2*(H3,1,2,3,4)
Chemical Name
N-(3,3-dimethyl-1,2-dihydroindol-6-yl)-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide;phosphoric acid
Synonyms
AMG-706; Motesanib Diphosphate; AMG 706; AMG706; motesanib phosphate;
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ~100 mg/mL (~175.6 mM)
Water: ~19 mg/mL (~33.4 mM)
Ethanol :<1 mg/mL
Solubility (In Vivo)
Saline: 30mg/mL
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 1.7561 mL 8.7806 mL 17.5611 mL
5 mM 0.3512 mL 1.7561 mL 3.5122 mL
10 mM 0.1756 mL 0.8781 mL 1.7561 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

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Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT05371964 Recruiting Drug: Imetelstat
Drug: Ruxolitinib
Myelofibrosis Geron Corporation May 4, 2022 Phase 1
NCT05583552 Recruiting Drug: Imetelstat Myelodysplastic Syndromes
Acute Myeloid Leukemia
GCP-Service International
West GmbH
June 5, 2023 Phase 2
NCT04576156 Recruiting Drug: Imetelstat
Drug: Best Available Therapy
(BAT)
Myelofibrosis Geron Corporation April 12, 2021 Phase 3
NCT02598661 Active
Recruiting
Drug: Imetelstat
Drug: Placebo
Myelodysplastic Syndromes Geron Corporation November 24, 2015 Phase 2
Phase 3
NCT00427349 Completed Drug: AMG 706
Drug: octreotide
Islet Cell Tumor
Neoplastic Syndrome
Eastern Cooperative Oncology
Group/td>
November 7, 2008 Phase 2
Biological Data
  • Motesanib Diphosphate (AMG-706)

    Motesanib in vitro activity on VEGFR2 signaling and interaction with radiation. Clin Cancer Res. 2010 Jul 15;16(14):3639-47.

  • Motesanib Diphosphate (AMG-706)

    Vascular distribution and tumor architecture in UM-SCC1 xenografts. Clin Cancer Res. 2010 Jul 15;16(14):3639-47.

  • Motesanib Diphosphate (AMG-706)

    Impact of motesanib on intratumoral hypoxia (pimonidazole), proliferation (Ki67), and vasculature (9F1). Clin Cancer Res. 2010 Jul 15;16(14):3639-47.

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