Home Protein Tyrosine Kinase VEGFR inhibitor Motesanib Diphosphate (AMG-706)

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Motesanib Diphosphate (AMG-706) VEGFR inhibitor

Cat.No.S1032

Motesanib Diphosphate (AMG-706) is a potent ATP-competitive inhibitor of VEGFR1/2/3 with IC50 of 2 nM/3 nM/6 nM, respectively. It shows similar activity against Kit (c-Kit) and is ~10-fold more selective for VEGFR than PDGFR and Ret. This compound is in Phase 3.
Motesanib Diphosphate (AMG-706) VEGFR inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 569.44

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Quality Control

Batch: Purity: 99.99%
99.99

Solubility

In vitro
Batch:

DMSO : 100 mg/mL (175.61 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : 19 mg/mL

Ethanol : Insoluble

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In vivo
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Chemical Information, Storage & Stability

Molecular Weight 569.44 Formula

C22H23N5O.2H3PO4

 Storage (From the date of receipt)
CAS No. 857876-30-3 Download SDF Storage of Stock Solutions

Synonyms N/A 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

Mechanism of Action

Targets/IC50/Ki
VEGFR1
(Cell-free assay)
2 nM
VEGFR2
(Cell-free assay)
3 nM
VEGFR2/Flk1
(Cell-free assay)
6 nM
VEGFR3
(Cell-free assay)
6 nM
Kit
(Cell-free assay)
8 nM
RET
(Cell-free assay)
59 nM
PDGFR
(Cell-free assay)
84 nM
In vitro

Motesanib Diphosphate (AMG-706) has broad activity against the human VEGFR family, and displays >1000 selectivity against EGFR, Src, and p38 kinase. It 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. This compound also potently inhibits PDGF-induced proliferation and SCF-induced c-kit phosphorylation with IC50 of 207 nM and 37 nM, respectively, but is not effective against the EGF-induced EGFR phosphorylation and cell viability of A431 cells. Althouth displaying little antiproliferative activity on cell growth of HUVECs alone, it significantly sensitizes the cells to fractionated radiation.

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. For Motesanib Diphosphate (AMG-706), a 10-point dose-response curve is tested 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.
In vivo

Motesanib Diphosphate (AMG-706) administration at 100 mg/kg significantly inhibits VEGF-induced vascular permeability in a time-dependent manner. Oral administration of this compound 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. It induces a dose-dependent tumor regression of established A431 xenografts by selectively targeting neovascularization in tumor cells. When administered in combination with radiation, it displays significant anti-tumor activity in head and neck squamous cell carcinoma (HNSCC) xenograft models. Treatment with this compound also induces significant dose-dependent reductions in tumor growth and blood vessel density of MCF-7, MDA-MB-231, or Cal-51 xenografts. 
References

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01386866 Completed
Advanced Solid Tumors
Amgen
 May 2009 Phase 1
NCT00448786 Completed
Solid Tumors
Amgen
 February 2007 Phase 1
NCT00322400 Completed
Locally Recurrent and Metastatic Breast Cancer
Amgen
 March 2006 Phase 1
NCT01235416 Completed
Histologically or Cytologically Documented Solid Tumors
Amgen
 September 2005 Phase 1

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