Motesanib Diphosphate

• Catalog No.: S1032
• CAS Number: 857876-30-3
• M. F.: C22H29N5O9P2
• M. W.: 569.441282
• Storage: -20°C

SYNONYMS

• IUPAC name: N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(pyridin-4-ylmethyl)amino]pyridine-3-carboxamide; bis(phosphoric acid)
• IUPAC Traditional name: motesanib; bis(phosphoric acid)
• Synonyms: AMG-706

DATABASE IDS

• CAS Number: 857876-30-3

PROPERTIES

• Target: VEGFR
• Target: PDGFR
• Target: c-Kit
• Salt Data: Diphosphate
• Solubility: DMSO
• Storage Condition: -20°C

DETAILS

Description (English)

Research Area

• Description: Cancer

Biological Activity

• Description: Motesanib Diphosphate (AMG-706) is a potent ATP-competitive inhibitor of VEGFR1/2/3, PDGFR, c-Kit and Ret with IC50 of 2 nM/3 nM/6 nM, 84 nM, 8 nM and 59 nM, respectively.
• Targets: VEGFR1; VEGFR2; VEGFR3; PDGFR; c-Kit; Ret
• IC50: 2 nM; 3 nM; 6 nM; 84 nM; 8 nM; 59 nM ^[1]
• 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]
• Clinical Trials: A Phase I study to evaluate the effect of different doses of Motesanib Diphosphate on the gallbladder in advanced solid tumors has been completed.

Protocol

• Protocol: 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 K_m 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.
• Protocol: Cell Assay ^[1]
• Cell Lines: A431, MO7e, HUVEC and NHDF cells
• Concentrations: Dissolved in DMSO, final concentrations ~25 μM
• Incubation Time: 2 hours
• Methods: 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 equation.
• Protocol: 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
• Doses: ~100 mg/kg
• Administration: Orally administered twice daily or once daily

References

• References: [1] Polverino A, et al. Cancer Res, 2006, 66(17), 8715-8721.
• References: [2] Kruser TJ, et al. Clin Cancer Res, 2010, 16(14), 3639-3647.
• References: [3] Coxon A, et al. Clin Cancer Res, 2009, 15(1), 110-118.

REFERENCES

• Polverino A, et al. Cancer Res, 2006, 66(17), 8715-8721.
• Kruser TJ, et al. Clin Cancer Res, 2010, 16(14), 3639-3647.
• Coxon A, et al. Clin Cancer Res, 2009, 15(1), 110-118.