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| 5mg |
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| 25mg |
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| 100mg |
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Purity: ≥98%
Motesanib (formerly also known as AMG-706) is a novel, potent, ATP-competitive, orally bioavailable inhibitor of VEGFR1/2/3 (vascular endothelial growth factor) with IC50 of 2 nM/3 nM/6 nM, respectively; it has potential anticancer activity; Motesanib shows similar activity against Kit, and ~10-fold more selective for VEGFR than PDGFR and Ret. By specifically targeting and blocking the VEGFR, PDGFR, kit, and Ret receptors, motesanib prevents angiogenesis and the growth of new cells.
| Targets |
VEGFR1 (IC50 = 2 nM); VEGFR2 (IC50 = 3 nM); VEGFR3 (IC50 = 6 nM)
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|---|---|
| ln Vitro |
Motesanib exhibits >1000 selectivity against EGFR, Src, and p38 kinase in addition to having broad activity against the human VEGFR family. With an IC50 of 10 nM, motesanib dramatically suppresses HUVECs' VEGF-induced cellular proliferation, but has minimal effect on bFGF-induced proliferation (IC50 of >3,000 nM). With an IC50 of 207 nM for PDGF-induced proliferation and 37 nM for SCF-induced c-kit phosphorylation, respectively, motesanib also potently inhibits these processes[1]. However, it is ineffective against EGF-induced EGFR phosphorylation and A431 cell viability. Despite having minimal effect on HUVECs' ability to proliferate, motesanib treatment greatly increases the cells' sensitivity to fractionated radiation[2].
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| ln Vivo |
Motesanib (100 mg/kg) significantly inhibits VEGF-induced vascular permeability in a time-dependent manner. Using the rat corneal model, oral administration of Motesanib 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 focusing on neovascularization in tumor cells, motesanib causes a dose-dependent tumor regression in well-established A431 xenografts[1]. In xenograft models of head and neck squamous cell carcinoma (HNSCC), motesanib in combination with radiation exhibits strong anti-tumor activity[2]. When used in conjunction with docetaxel or tamoxifen, motesanib treatment also significantly reduces the tumor growth and blood vessel density of MCF-7, MDA-MB-231, or Cal-51 xenografts in a dose-dependent manner[3].
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| 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.
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| 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.
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| Animal Protocol |
Penicillin, streptomycin, and glutamine are added to 10% FBS-containing DMEM (low glucose) medium for the cultivation of A431 cells. Trypsinization is used to extract the cells, which are then cleaned and concentrated to 5×107/mL in serum-free medium. Animals are given 1x107 cells in 0.2 mL over their left flank as a challenge. A little over ten days later, mice are treated with either vehicle (Ora-Plus) or motesanib, randomly assigned according to initial tumor volume measurements. Body weights and tumor volumes are noted once a week, as well as on the day of sacrifice. The Pro-Max electronic digital caliper is used to measure the tumor volume, which is then computed using the formula length (mm)×width (mm)×height (mm) and expressed in mm3. The data are 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 afterwards.
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| References |
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| Molecular Formula |
C22H23N5O
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|---|---|
| Molecular Weight |
373.460
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| Exact Mass |
373.19
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| Elemental Analysis |
C, 70.76; H, 6.21; N, 18.75; O, 4.28
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| CAS # |
453562-69-1
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| Related CAS # |
Motesanib Diphosphate;857876-30-3
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| Appearance |
White to off-white solid powder
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| SMILES |
CC1(CNC2=C1C=CC(=C2)NC(=O)C3=C(N=CC=C3)NCC4=CC=NC=C4)C
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| InChi Key |
RAHBGWKEPAQNFF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H23N5O/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/h3-12,26H,13-14H2,1-2H3,(H,24,25)(H,27,28)
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| Chemical Name |
N-(3,3-dimethyl-1,2-dihydroindol-6-yl)-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide
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| Synonyms |
motesanib free base; AMG-706; AMG 706; AMG706
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.69 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.69 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6777 mL | 13.3883 mL | 26.7766 mL | |
| 5 mM | 0.5355 mL | 2.6777 mL | 5.3553 mL | |
| 10 mM | 0.2678 mL | 1.3388 mL | 2.6777 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.
Calculation results
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.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02598661 | Active Recruiting |
Drug: Imetelstat Drug: Placebo |
Myelodysplastic Syndromes | Geron Corporation | November 24, 2015 | Phase 2 Phase 3 |
| NCT04576156 | Recruiting | Drug: Imetelstat Drug: Best Available Therapy (BAT) |
Myelofibrosis | Geron Corporation | April 12, 2021 | Phase 3 |
| NCT05583552 | Recruiting | Drug: Imetelstat | Myelodysplastic Syndromes Acute Myeloid Leukemia |
GCP-Service International West GmbH |
June 5, 2023 | Phase 2 |
| NCT05371964 | Recruiting | Drug: Imetelstat Drug: Ruxolitinib |
Myelofibrosis | Geron Corporation | May 4, 2022 | Phase 1 |
Motesanib in vitro activity on VEGFR2 signaling and interaction with radiation. Clin Cancer Res. 2010 Jul 15;16(14):3639-47. |
Vascular distribution and tumor architecture in UM-SCC1 xenografts. Clin Cancer Res. 2010 Jul 15;16(14):3639-47. |
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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