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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. Its IC50s are 2 nM, 3 nM, and 6 nM for VEGFR1/2/3 inhibition, respectively.
| Targets |
VEGFR1 (IC50 = 2 nM); VEGFR2 (IC50 = 3 nM); VEGFR2/Flk1 (IC50 = 6 nM); VEGFR3 (IC50 = 6 nM); Kit (IC50 = 8 nM)
Motesanib Diphosphate (AMG-706) inhibits VEGFR1 (IC₅₀ = 2 nM), VEGFR2 (IC₅₀ = 3 nM), VEGFR3 (IC₅₀ = 6 nM), PDGFRα (IC₅₀ = 21 nM), PDGFRβ (IC₅₀ = 14 nM), and c-Kit (IC₅₀ = 26 nM) [1] Motesanib Diphosphate (AMG-706) shows no significant inhibition against EGFR, FGFR, or RET (IC₅₀ > 1000 nM) [3] |
|---|---|
| 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].
Motesanib Diphosphate (AMG-706) dose-dependently inhibited VEGF-induced proliferation of human umbilical vein endothelial cells (HUVECs) with an IC₅₀ of 18 nM. At 100 nM, it suppressed HUVEC migration by ~85% and tube formation by ~90%, and blocked VEGF-mediated phosphorylation of VEGFR2 and downstream Akt/ERK signaling [1] Motesanib Diphosphate (AMG-706) enhanced the radiosensitivity of non-small cell lung cancer (NSCLC) cells (A549) in vitro. Combination of 50 nM motesanib with 2 Gy radiation increased cell apoptosis by ~40% compared to radiation alone, and downregulated radiation-induced VEGF secretion [2] Motesanib Diphosphate (AMG-706) inhibited the proliferation of c-Kit-positive breast cancer cells (MDA-MB-453) with an IC₅₀ of 3.2 μM. It blocked PDGF-BB-induced PDGFRβ phosphorylation in breast cancer-associated fibroblasts at 100 nM [3] |
| 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].
Motesanib Diphosphate (AMG-706) induced tumor regression in nude mice bearing Colo205 colorectal cancer xenografts when administered orally at 50 mg/kg/day for 28 days. Tumor volume was reduced by ~75% compared to the control group, and intratumoral microvessel density (CD31-positive) decreased by ~80% [1] Motesanib Diphosphate (AMG-706) augmented the antitumor effect of radiation in nude mice bearing A549 NSCLC xenografts. Oral administration of 30 mg/kg/day motesanib plus 8 Gy radiation (fractionated over 4 days) reduced tumor volume by ~85% compared to radiation alone, and prolonged median survival by 50% [2] Motesanib Diphosphate (AMG-706) suppressed the growth of multiple breast cancer xenografts (MDA-MB-231, BT-474) in nude mice. Oral doses of 25-50 mg/kg/day for 21 days resulted in tumor growth inhibition rates of 60-75%, and reduced lung metastasis of MDA-MB-231 cells by ~65% [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.
Recombinant VEGFR1, VEGFR2, VEGFR3, PDGFRα, PDGFRβ, and c-Kit kinase domains were individually incubated with ATP and specific peptide substrates in the presence of serial dilutions of Motesanib Diphosphate (AMG-706). Reactions were carried out at 37°C for 60 minutes, and phosphorylated substrates were detected using a homogeneous time-resolved fluorescence (HTRF) assay. Inhibition rates were calculated by comparing fluorescence intensity with vehicle controls, and IC₅₀ values were derived from dose-response curves [1] To assess selectivity, the same protocol was used to test inhibitory activity against recombinant EGFR, FGFR, and RET kinases. Reaction conditions were identical, and IC₅₀ values were determined to confirm selective targeting of VEGFR, PDGFR, and c-Kit [3] |
| 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.
HUVECs were seeded in 96-well plates at 5×10³ cells/well and cultured overnight. Motesanib Diphosphate (AMG-706) (1-200 nM) was added 1 hour before stimulation with VEGF (50 ng/mL). After 72 hours, cell viability was measured using a tetrazolium-based assay to calculate IC₅₀. For Western blot, HUVECs were treated with 20-100 nM drug and VEGF, then lysed and probed with antibodies against phosphorylated VEGFR2, Akt, ERK1/2, and GAPDH [1] A549 cells were seeded in 96-well plates and treated with Motesanib Diphosphate (AMG-706) (10-100 nM) for 24 hours, followed by radiation (0-4 Gy). After 72 hours, cell viability was assessed by MTT assay. Apoptosis was detected by Annexin V-FITC/PI staining, and VEGF secretion was measured by ELISA [2] MDA-MB-453 cells and breast cancer-associated fibroblasts were treated with Motesanib Diphosphate (AMG-706) (0.1-10 μM) for 48 hours. Cell viability was measured by CCK-8 assay. Western blot was used to detect phosphorylated PDGFRβ and c-Kit in respective cell types [3] |
| 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 5×10 7 /mL in serum-free medium. 1x10 7 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 (mm 3 ) 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].
Nude mice bearing Colo205 colorectal cancer xenografts (100-150 mm³) were randomly divided into control and treatment groups. Motesanib Diphosphate (AMG-706) was suspended in 0.5% carboxymethylcellulose and administered orally at 50 mg/kg/day for 28 days. Tumor volume was measured every 3 days, and mice were euthanized to collect tumors for CD31 immunostaining [1] Nude mice bearing A549 NSCLC xenografts were assigned to four groups: control, motesanib alone (oral, 30 mg/kg/day), radiation alone (8 Gy, fractionated as 2 Gy/day for 4 days), and combination group. Motesanib was administered for 14 days (starting 3 days before radiation). Tumor volume was measured twice weekly, and survival time was recorded [2] Nude mice bearing MDA-MB-231 or BT-474 breast cancer xenografts were treated with Motesanib Diphosphate (AMG-706) orally at 25 or 50 mg/kg/day for 21 days. Tumor weight and volume were recorded weekly. For metastasis assessment, MDA-MB-231-inoculated mice were treated for 28 days, and lungs were harvested to count metastatic nodules [3] |
| ADME/Pharmacokinetics |
In mice, the bioavailability of a single oral dose of 50 mg/kg motesanil diphosphate (AMG-706) is approximately 57%. The plasma half-life is approximately 8.3 hours, and the maximum plasma concentration (Cmax) is 4.2 μg/mL 2 hours after administration [1]. In rats, the 24-hour AUC₀ of oral administration of 30 mg/kg motesanil diphosphate (AMG-706) is 36.8 μg·h/mL. The drug is widely distributed in the liver, kidneys and tumor tissues, with a tumor/plasma concentration ratio of approximately 3.1 [3].
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| Toxicity/Toxicokinetics |
Mice treated with motexanil diphosphate (AMG-706) at a dose of 50 mg/kg/day for 28 days showed mild weight loss (approximately 10%) and transient diarrhea (18% of animals), but no significant hepatotoxicity or nephrotoxicity was observed. Serum ALT, AST, and creatinine levels were all within the normal range [1]. When used in combination with radiotherapy, the toxicity in mice was not increased compared to monotherapy, and no serious hematological abnormalities or gastrointestinal complications occurred [2]. The plasma protein binding rate of motexanil diphosphate (AMG-706) in human plasma was approximately 91% as determined by balanced dialysis [3].
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| References |
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| Additional Infomation |
Modesanil diphosphate is a highly bioavailable oral multi-receptor tyrosine kinase inhibitor diphosphate with potential antitumor activity. Modesanil selectively targets and inhibits vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), kit, and Ret receptors, thereby inhibiting angiogenesis and cell proliferation. See also: Modesanil (note moved to). Modesanil diphosphate (AMG-706) is a highly selective oral multi-kinase inhibitor that exerts its antitumor effect by blocking VEGFR-mediated angiogenesis, PDGFR-driven matrix support, and c-Kit-dependent tumor cell proliferation [1]. Modesanil diphosphate (AMG-706)'s ability to enhance radioresponsiveness makes it an ideal candidate for combination therapy with radiotherapy for locally advanced solid tumors [2].
Motesanib diphosphate (AMG-706) exhibits broad antitumor activity against various breast cancer subtypes, especially those with VEGF dysregulation. PDGF or c-Kit signaling pathways [3] |
| Molecular Formula |
C22H29N5O9P2
|
|---|---|
| Molecular Weight |
569.44
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| Exact Mass |
569.144
|
| Elemental Analysis |
C, 46.40; H, 5.13; N, 12.30; O, 25.29; P, 10.88
|
| CAS # |
857876-30-3
|
| Related CAS # |
Motesanib;453562-69-1
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| PubChem CID |
16097729
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| Appearance |
White to off-white solid powder
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| Boiling Point |
858.7ºC at 760 mmHg
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| Flash Point |
473.1ºC
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| LogP |
2.781
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| Hydrogen Bond Donor Count |
9
|
| Hydrogen Bond Acceptor Count |
13
|
| Rotatable Bond Count |
5
|
| Heavy Atom Count |
38
|
| Complexity |
583
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
P(=O)(O[H])(O[H])O[H].P(=O)(O[H])(O[H])O[H].O=C(C1C([H])=C([H])C([H])=NC=1N([H])C([H])([H])C1C([H])=C([H])N=C([H])C=1[H])N([H])C1C([H])=C([H])C2=C(C=1[H])N([H])C([H])([H])C2(C([H])([H])[H])C([H])([H])[H]
|
| 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
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| Synonyms |
AMG-706; Motesanib Diphosphate; AMG 706; AMG706; motesanib phosphate;
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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: ≥ 25 mg/mL (43.90 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 250.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.39 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.39 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. Solubility in Formulation 4: Saline: 30mg/mL |
| 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.
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 |
| 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 |
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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