Motesanib Diphosphate (AMG-706)

 

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Biological Activity

Description	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, ~10-fold more selective for VEGFR than PDGFR and Ret. Phase 1/2.
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]
Features

Protocol(Only for Reference)

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 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 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.

Cell Assay: ^[1]

Cell lines	A431, MO7e, HUVEC and NHDF cells
Concentrations	Dissolved in DMSO, final concentrations ~25 μM
Incubation Time	2 hours
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 equatio

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
Dosages	~100 mg/kg
Administration	Orally administered twice daily or once daily
Solubility	Saline, 30 mg/mL

1

References

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number	Recruitment	Conditions	Sponsor /Collaborators	Start Date	Phases
NCT00574951	Active, not recruiting	Fallopian Tube Cancer|Ovarian Cancer|Primary Peritoneal Cavity Cancer	National Cancer Institute (NCI)|Gynecologic Oncology Group	2007-12	Phase 2
NCT00427349	Active, not recruiting	Gastrointestinal Carcinoid Tumor|Islet Cell Tumor|Neoplastic Syndrome	National Cancer Institute (NCI)|Eastern Cooperative Oncology Group	2008-09	Phase 2
NCT01386866	Completed	Advanced Solid Tumors	Amgen	2009-05	Phase 1
NCT01700699	Recruiting	Differentiated Thyroid Cancer	University of Salerno	2012-10
NCT01349088	Not yet recruiting	Breast Cancer|Metastatic Breast Cancer|Stage IV Breast Cancer	Thomas Jefferson University|Susan G. Komen Breast Cancer Foundation|Amgen	2013-12	Phase 1|Phase 2

Chemical Information

Download Motesanib Diphosphate (AMG-706) SDF

Chemical Name	3-Pyridinecarboxamide, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-, phosphate (1:2)

Preparing Stock Solutions

Stock Solution (1ml DMSO)	1mM	10mM	20mM	30mM
Mass(mg)	0.56944	5.6944	11.3888	17.0832

Customer Reviews (2)

Click to enlarge	Rating
	Source	Cardiovasc Res. Motesanib Diphosphate (AMG-706) purchased from Selleck
	Method	FACS analysis
	Cell Lines	cardiac stem cell (CSC)
	Concentrations	2 nM
	Incubation Time	30 min
	Results	All VEGFR inhibitors (incuding AMG-706, inhibited VEGFCM-mediated CSC migration.

Product Citations (2)

• 
  

  VEGF/SDF-1 promotes cardiac stem cell mobilization and myocardial repair in the infarcted heart. [Tang JM, et al. Cardiovasc Res 2011;91(3):402-11]

  
  PubMed: 21345805


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  Ponatinib is a potent inhibitor of wild-type and drug-resistant gatekeeper mutant RET kinase. [Mologni L, et al. Mol Cell Endocrinol 2013;377(1-2):1-6]

  
  PubMed: 23811235