1. Protein Tyrosine Kinase/RTK
  2. c-Kit
    VEGFR

Motesanib (Synonyms: AMG 706; )

Cat. No.: HY-10228 Purity: 99.93%
Data Sheet SDS Handling Instructions

Motesanib is a potent ATP-competitive inhibitor of VEGFR1/2/3 with IC50s of 2 nM/3 nM/6 nM, respectively, and has similar activity against Kit, and is appr 10-fold more selective for VEGFR than PDGFR and Ret. 

For research use only. We do not sell to patients.
Motesanib Chemical Structure

Motesanib Chemical Structure

CAS No. : 453562-69-1

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10 mM * 1 mL in DMSO $55 In-stock
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50 mg $160 In-stock
100 mg $280 In-stock
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Other Forms of Motesanib:

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  • Biological Activity

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Description

Motesanib is a potent ATP-competitive inhibitor of VEGFR1/2/3 with IC50s of 2 nM/3 nM/6 nM, respectively, and has similar activity against Kit, and is appr 10-fold more selective for VEGFR than PDGFR and Ret. 

IC50 & Target

IC50: 2 nM (VEGFR1), 3 nM (VEGFR2), 6 nM (VEGFR3)

In Vitro

Motesanib has broad activity against the human VEGFR family, and displays > 1000 selectivity against EGFR, Src, and p38 kinase. Motesanib 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 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 treatment significantly sensitizes the cells to fractionated radiation[2]

In Vivo

Motesanib (100 mg/kg) significantly inhibits VEGF-induced vascular permeability in a time-dependent manner. Oral administration of Motesanib 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 induces a dose-dependent tumor regression of established A431 xenografts by selectively targeting neovascularization in tumor cells[1]. Motesanib in combination with radiation displays significant anti-tumor activity in head and neck squamous cell carcinoma (HNSCC) xenograft models[2]. Motesanib 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]

Clinical Trial
NCT Number Sponsor Condition Start Date Phase
NCT00254267 Amgen|Takeda Bio Development Center, Ltd Advanced Gastrointestinal Stromal Tumor November 2005 Phase 2
NCT00427349 Eastern Cooperative Oncology Group|National Cancer Institute (NCI) Gastrointestinal Carcinoid Tumor|Islet Cell Tumor|Neoplastic Syndrome September 2008 Phase 2
NCT01386866 Amgen Advanced Solid Tumors May 2009 Phase 1
NCT00360867 Amgen Solid Tumors December 2005 Phase 2
NCT00093873 Amgen Tumors July 2003 Phase 1
NCT01235416 Amgen Histologically or Cytologically Documented Solid Tumors September 2005 Phase 1
NCT00089960 Amgen Gastrointestinal Cancer October 2004 Phase 2
NCT00101894 Amgen Rectal Cancer|Colon Cancer December 2004 Phase 1
NCT00448786 Amgen Solid Tumors February 2007 Phase 1
NCT00356681 Amgen Breast Neoplasms|Breast Tumors|Breast Cancer|Locally Recurrent and Metastatic Breast Cancer December 2006 Phase 2
NCT00369070 Amgen Advanced Non-squamous NSCLC January 2007 Phase 2
NCT00121628 Amgen Thyroid Cancer July 2005 Phase 2
NCT00101907 Amgen Lung Cancer|Pancreatic Cancer|Esophageal Cancer December 2004 Phase 1
NCT00322400 Amgen Locally Recurrent and Metastatic Breast Cancer March 2006 Phase 1
NCT00861419 Amgen Advanced Solid Tumors December 2005 Phase 1
NCT00460317 Amgen|Takeda Non-Small Cell Lung Cancer July 2007 Phase 3
NCT00254267 Amgen|Takeda Bio Development Center, Ltd Advanced Gastrointestinal Stromal Tumor November 2005 Phase 2
NCT00427349 Eastern Cooperative Oncology Group|National Cancer Institute (NCI) Gastrointestinal Carcinoid Tumor|Islet Cell Tumor|Neoplastic Syndrome September 2008 Phase 2
NCT01386866 Amgen Advanced Solid Tumors May 2009 Phase 1
NCT00360867 Amgen Solid Tumors December 2005 Phase 2
NCT00093873 Amgen Tumors July 2003 Phase 1
NCT01235416 Amgen Histologically or Cytologically Documented Solid Tumors September 2005 Phase 1
NCT00089960 Amgen Gastrointestinal Cancer October 2004 Phase 2
NCT00101894 Amgen Rectal Cancer|Colon Cancer December 2004 Phase 1
NCT00448786 Amgen Solid Tumors February 2007 Phase 1
NCT00356681 Amgen Breast Neoplasms|Breast Tumors|Breast Cancer|Locally Recurrent and Metastatic Breast Cancer December 2006 Phase 2
NCT00369070 Amgen Advanced Non-squamous NSCLC January 2007 Phase 2
NCT00121628 Amgen Thyroid Cancer July 2005 Phase 2
NCT00101907 Amgen Lung Cancer|Pancreatic Cancer|Esophageal Cancer December 2004 Phase 1
NCT00322400 Amgen Locally Recurrent and Metastatic Breast Cancer March 2006 Phase 1
NCT00861419 Amgen Advanced Solid Tumors December 2005 Phase 1
NCT00460317 Amgen|Takeda Non-Small Cell Lung Cancer July 2007 Phase 3
NCT02629848 Takeda Carcinoma, Non-Small-Cell Lung July 2012 Phase 3
NCT00094835 Amgen Lung Cancer|Non-Small Cell Lung Cancer January 2005 Phase 1|Phase 2
NCT01349088 Sidney Kimmel Cancer Center at Thomas Jefferson University|Susan G. Komen Breast Cancer Foundation|Amgen|Thomas Jefferson University Breast Cancer|Metastatic Breast Cancer|Stage IV Breast Cancer December 2013 Phase 1|Phase 2
NCT00574951 Gynecologic Oncology Group|National Cancer Institute (NCI) Fallopian Tube Cancer|Ovarian Cancer|Primary Peritoneal Cavity Cancer December 2007 Phase 2
NCT00324597 Jonsson Comprehensive Cancer Center|National Cancer Institute (NCI) Lung Cancer|Lymphoma|Lymphoproliferative Disorder|Unspecified Adult Solid Tumor, Protocol Specific October 2005 Phase 1
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References
Preparing Stock Solutions
Concentration Volume (DMSO) Mass 1 mg 5 mg 10 mg
1 mM 2.6777 mL 13.3887 mL 26.7773 mL
5 mM 0.5355 mL 2.6777 mL 5.3555 mL
10 mM 0.2678 mL 1.3389 mL 2.6777 mL
Kinase Assay
[1]

Optimal enzyme, ATP, and substrate (gastrin peptide) concentrations are established for each enzyme using homogeneous time-resolved fluorescence (HTRF) assays. Motesanib 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. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Assay
[1]

Cells are preincubated for 2 hours with different concentrations of Motesanib, 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. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[1]

Motesanib is formulated in Ora-Plus.

A431 cells are cultured in DMEM (low glucose) with 10% FBS and penicillin/streptomycin/glutamine. Cells are harvested by trypsinization, washed, and adjusted to a concentration of 5×107/mL in serum-free medium. Animals are challenged s.c. with 1×107 cells in 0.2 mL over the left flank. Approximately 10 days thereafter, mice are randomized based on initial tumor volume measurements and treated with either vehicle (Ora-Plus) or Motesanib. Tumor volumes and body weights are recorded twice weekly and/or on the day of sacrifice. Tumor volume is measured with a Pro-Max electronic digital caliper and calculated using the formula length (mm)×width (mm)×height (mm) and expressed in mm3. Data are expressed as mean±SE. Repeated measures ANOVA followed by Scheffe post hoc testing for multiple comparisons is used to evaluate the statistical significance of observed differences. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

References
M.Wt

373.45

Formula

C₂₂H₂₃N₅O

CAS No.

453562-69-1

Storage
Powder -20°C 3 years
  4°C 2 years
In solvent -80°C 6 months
  -20°C 1 month
Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

DMSO: ≥ 30 mg/mL

* "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

Purity: 99.93%

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Motesanib
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