Home Protein Tyrosine Kinase VEGFR inhibitor - PDGFR inhibitor - c-Kit 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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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

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

Molarity Calculator

Mass Concentration Volume Molecular Weight

In vivo
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Mechanism of Action

Targets/IC50/Ki
VEGFR1 [1]
(Cell-free assay)
2 nM
VEGFR2 [1]
(Cell-free assay)
3 nM
VEGFR2/Flk1 [1]
(Cell-free assay)
6 nM
VEGFR3 [1]
(Cell-free assay)
6 nM
Kit [1]
(Cell-free assay)
8 nM
RET [1]
(Cell-free assay)
59 nM
PDGFR [1]
(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. [1] Althouth displaying little antiproliferative activity on cell growth of HUVECs alone, it significantly sensitizes the cells to fractionated radiation. [2]
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. [1] When administered in combination with radiation, it displays significant anti-tumor activity in head and neck squamous cell carcinoma (HNSCC) xenograft models. [2] 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. [3]
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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