莫替沙尼作用机制 - Medchemexpress - MCE中国

1、Product Data SheetMotesanibCat. No.: HY-10228CAS No.: 453562-69-1分式: CHNO分量: 373.45作靶点: c-Kit; VEGFR作通路: Protein Tyrosine Kinase/RTK储存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性数据体外实验 DMSO : 100 mg/mL (267.77 mM)* means soluble, but saturation unknown.SolventMass1 mg 5 mg

2、 10 mgConcentration制备储备液1 mM 2.6777 mL 13.3887 mL 26.7773 mL5 mM 0.5355 mL 2.6777 mL 5.3555 mL10 mM 0.2678 mL 1.3389 mL 2.6777 mL请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；旦配成溶液，请分装保存，避免反复冻融造成的产品失效。储备液的保存式和期限：-80C, 6 months; -20C, 1 month。-80C 储存时，请在 6 个内使，-20C 储存时，请在 1 个内使。体内实验请根据您的实验动物和给药式选择适当的溶解案。以下溶解案都请先按照 In

3、Vitro 式配制澄清的储备液，再依次添加助溶剂：为保证实验结果的可靠性，澄 的储备液可以根据储存条件，适当保存；体内实验的作液，建议您现现配，当天使； 以下溶剂前显的百分 指该溶剂在您配制终溶液中的体积占；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的式助溶1. 请依序添加每种溶剂： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (6.69 mM); Clear solution此案可获得 2.5 mg/mL (6.69 mM，饱和度未知) 的澄清溶液。以 1 mL 作液为例，取 100 L 25.

4、0 mg/mL 的澄 DMSO 储备液加到 400 L PEG300 中，混合均匀；向上述体系中加50 L Tween-80，混合均匀；然后继续加 450 L 理盐定容 1 mL。2. 请依序添加每种溶剂： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (6.69 mM); Clear solutionPage 1 of 2 www.MedChemE此案可获得 2.5 mg/mL (6.69 mM，饱和度未知) 的澄清溶液。以 1 mL 作液为例，取 100 L 25.0 mg/mL 的澄 DMSO 储备液加到 900 L 2

5、0% 的 SBE-CD 理盐溶液中，混合均匀。BIOLOGICAL ACTIVITY物活性 Motesanib 种有效的 VEGFR1/2/3 的 ATP 竞争性抑制剂，IC50 值为 2 nM/3 nM/6 nM，与对Kit的选择性相似，是 PDGFR 和 Ret的 10 倍多。IC & Target VEGFR1 VEGFR2 VEGFR32 nM (IC50) 3 nM (IC50) 6 nM (IC50)体外研究 Motesanib has broad activity against the human VEGFR family, and displays 1000 selectiv

6、ity against EGFR, Src, andp38 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 inhibitsPDGF-induced proliferation and SCF-induced

7、 c-kit phosphorylation with IC50 of 207 nM and 37 nM, respectively, butnot effective against the EGF-induced EGFR phosphorylation and cell viability of A431 cells1. Althouth displayinglittle antiproliferative activity on cell growth of HUVECs alone, Motesanib treatment significantly sensitizes the c

8、ells tofractionated radiation2.体内研究 Motesanib (100 mg/kg) significantly inhibits VEGF-induced vascular permeability in a time-dependent manner. Oraladministration of Motesanib twice daily or once daily potently inhibits, in a dose-dependent manner, VEGF-inducedangiogenesis using the rat corneal mode

9、l with ED50 of 2.1 mg/kg and 4.9 mg/kg, respectively. Motesanib induces adose-dependent tumor regression of established A431 xenografts by selectively targeting neovascularization in tumorcells1. Motesanib in combination with radiation displays significant anti-tumor activity in head and neck squamo

10、uscell carcinoma (HNSCC) xenograft models2. Motesanib treatment also induces significant dose-dependentreductions in tumor growth and blood vessel density of MCF-7, MDA-MB-231, or Cal-51 xenografts, which can bemarkedly enhanced when combined with docetaxel or tamoxifen3.PROTOCOLKinase Assay 1 Optim

11、al enzyme, ATP, and substrate (gastrin peptide) concentrations are established for each enzyme usinghomogeneous time-resolved fluorescence (HTRF) assays. Motesanib is tested in a 10-point dose-response curve foreach enzyme using an ATP concentration of two-thirds Km for each. Most assays consist of

12、enzyme mixed with kinasereaction buffer 20 mM Tris-HCl (pH 7.5), 10 mM MgCl2, 5 mM MnCl2, 100 mM NaCl, 1.5 mM EGTA. A finalconcentration of 1 mM DTT, 0.2 mM NaVO4, and 20 g/mL BSA is added before each assay. For all assays, 5.75mg/mL streptavidin-allophycocyanin and 0.1125 nM Eu-PT66 are added immed

13、iately before the HTRF reaction. Platesare incubated for 30 minutes at room temperature and read on a Discovery instrument. IC50 values are calculatedusing the Levenberg-Marquardt algorithm into a four-parameter logistic equation.MCE has not independently confirmed the accuracy of these methods. The

14、y 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 or20 ng/mL bFGF for an additional 72 hours. Cells are washed twice with DPBS, and plates are frozen at -70C for 24hours. Proliferation is assessed by th

15、e addition of CyQuant dye, and plates are read on a Victor 1420 workstation. IC50data 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.Page 2 of 3 www.MedChemEA

16、nimal A431 cells are cultured in DMEM (low glucose) with 10% FBS and penicillin/streptomycin/glutamine. Cells areAdministration 1 harvested by trypsinization, washed, and adjusted to a concentration of 5107/mL in serum-free medium. Animalsare challenged s.c. with 1107 cells in 0.2 mL over the left f

17、lank. Approximately 10 days thereafter, mice arerandomized 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 ismeasured with a Pro-Max electronic dig

18、ital caliper and calculated using the formula length (mm)width(mm)height (mm) and expressed in mm3. Data are expressed as meanSE. Repeated measures ANOVA followed byScheffe post hoc testing for multiple comparisons is used to evaluate the statistical significance of observeddifferences.MCE has not i

19、ndependently confirmed the accuracy of these methods. They are for reference only.户使本产品发表的科研献 Sci Transl Med. 2018 Jul 18;10(450). pii: eaaq1093. Cell Physiol Biochem. 2018;48(1):227-236. J Cell Biochem. 2019 Oct 21. Oncotarget. 2016 Sep 27;7(39):63839-63855. Harvard Medical School LINCS LIBRARYSee

20、more customer validations on HYPERLINK www.MedChemE www.MedChemEREFERENCES1. Polverino A, et al. AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, andkit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer R2. K