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Motesanib Diphosphate (AMG-706)

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.

Motesanib Diphosphate (AMG-706)化学構造

CAS No. 857876-30-3

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Motesanib Diphosphate (AMG-706)関連製品

シグナル伝達経路

VEGFR Signaling Pathways

VEGFRシグナル伝達経路

VEGFR阻害剤の選択性比較

生物活性

製品説明 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.
Targets
VEGFR1
(Cell-free assay)		 VEGFR2
(Cell-free assay)		 VEGFR2/Flk1
(Cell-free assay)		 VEGFR3
(Cell-free assay)		 Kit
(Cell-free assay)		 もっとクリックする
2 nM 3 nM 6 nM 6 nM 8 nM
In Vitro
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.
細胞実験 細胞株 A431, MO7e, HUVEC and NHDF cells
濃度 Dissolved in DMSO, final concentrations ~25 μM
反応時間 2 hours
実験の流れ

Cells are preincubated for 2 hours with different concentrations of Motesanib Diphosphate (AMG-706), and exposed with 50 ng/mL VEGF or 20 ng/mL bFGF for an additional 72 hours. After washing twice with DPBS, 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.
In Vivo
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. 
動物実験 動物モデル Female Sprague-Dawley rats with induced corneal angiogenesis, and female CD-1 nu/nu mice injected s.c. with A431 cells
投与量 ~100 mg/kg
投与経路 Orally administered twice daily or once daily
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
  • https://pubmed.ncbi.nlm.nih.gov/16951187/
  • https://pubmed.ncbi.nlm.nih.gov/20507929/
  • https://pubmed.ncbi.nlm.nih.gov/19118038/

化学情報

分子量 569.44 化学式

C22H23N5O.2H3PO4
CAS No. 857876-30-3 SDF Download Motesanib Diphosphate (AMG-706) SDFをダウンロードする
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
保管

In vitro
Batch:

DMSO : 100 mg/mL ( (175.61 mM)； 吸湿したDMSOは溶解度を減少させます。新しいDMSOをご使用ください。)

Water : 19 mg/mL

Ethanol : Insoluble

モル濃度計算器

in vivo
Batch:

Add solvents to the product individually and in order.

投与溶液組成計算機

実験計算

モル濃度計算器

質量 濃度 体積 分子量

投与溶液組成計算機(クリア溶液)

ステップ１：実験データを入力してください。（実験操作によるロスを考慮し、動物数を1匹分多くして計算・調製することを推奨します）

mg/kg g μL 匹

ステップ２：投与溶媒の組成を入力してください。（ロット毎に適した溶解組成が異なる場合があります。詳細については弊社までお問い合わせください）

% DMSO % % Tween 80 % ddH2O
%DMSO %

計算結果：

投与溶媒濃度： mg/ml;

DMSOストック溶液調製方法： mg 試薬を μL DMSOに溶解する（濃度 mg/mL, 注：濃度が当該ロットのDMSO溶解度を超える場合はご連絡ください。 )

投与溶媒調製方法：Take μL DMSOストック溶液に μL PEG300，を加え、完全溶解後μL Tween 80，を加えて完全溶解させた後 μL ddH2O，を加え完全に溶解させます。

投与溶媒調製方法：μL DMSOストック溶液に μL Corn oil，を加え、完全溶解。

注意：１.ストック溶液に沈殿、混濁などがないことをご確認ください；
２.順番通りに溶剤を加えてください。次のステップに進む前に溶液に沈殿、混濁などがないことを確認してから加えてください。ボルテックス、ソニケーション、水浴加熱など物理的な方法で溶解を早めることは可能です。

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