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Motesanib Diphosphate (AMG-706)

Motesanib Diphosphate (AMG-706)

Item no.	S1032-10
Manufacturer	Selleckchem
CASRN	857876-30-3
Amount	10 mg
Quantity options	10 mg 1 g 10 g 10 mM/1 ml 200 mg 5 mg 50 mg 5 g
Category	Oncology Neuroscience Neural Signaling Inhibitors & Compound Libraries Small Molecules By Organ Skin Cancer Bladder Cancer
Type	Inhibitors
Specific against	other
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
ECLASS 10.1	32160490
ECLASS 11.0	32160490
UNSPSC	12000000
Alias	857876-30-3'
Similar products	Motesanib
Available
Manufacturer - Targets	RET, KIT
Storage Conditions	2 years -80 in solvent
Molecular Weight	569, 44
Administration	Orally administered twice daily or once daily
Animal Models	Female Sprague-Dawley rats with induced corneal angiogenesis, and female CD-1 nu/nu mice injected s.c. with A431 cells
Cell lines	A431, MO7e, HUVEC and NHDF cells
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.
Concentrations	Dissolved in DMSO, final concentrations ca.25 uM
Dosages	ca.100 mg/kg
Formulation	Formulated as a suspension in Ora-Plus vehicle adjusted to pH 2.0
IC50	2 nM, 2 nM, 2 nM, 2 nM, 2 nM, 2 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, which can be markedly enhanced when combined with docetaxel or tamoxifen. [3]
Incubation Time	2 hours
Kinase Assay	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 ug/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.
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 equation.
Solubility (25C)	DMSO 114 mg/mL, Water 114 mg/mL, Ethanol <1 mg/mL
Information	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.
Chemical Name	3-Pyridinecarboxamide, N-(2, 3-dihydro-3, 3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-, phosphate (1:2)

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S1032-10-datasheet.pdf

S1032-10-safety-datasheet.pdf