莫替沙尼作用機制 - Medchemexpress - MCE中國

1、Product Data SheetMotesanibCat. No.: HY-10228CAS No.: 453562-69-1分式: CHNO分量: 373.45作靶點: c-Kit; VEGFR作通路: Protein Tyrosine Kinase/RTK儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實驗 DMSO : 100 mg/mL (267.77 mM)* means soluble, but saturation unknown.SolventMass1 mg 5 mg

2、 10 mgConcentration制備儲備液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請根據(jù)產(chǎn)品在不同溶劑中的溶解度選擇合適的溶劑配制儲備液；旦配成溶液，請分裝保存，避免反復凍融造成的產(chǎn)品失效。儲備液的保存式和期限：-80C, 6 months; -20C, 1 month。-80C 儲存時，請在 6 個內(nèi)使，-20C 儲存時，請在 1 個內(nèi)使。體內(nèi)實驗請根據(jù)您的實驗動物和給藥式選擇適當?shù)娜芙獍?。以下溶解案都請先按?In

3、Vitro 式配制澄清的儲備液，再依次添加助溶劑：為保證實驗結(jié)果的可靠性，澄 的儲備液可以根據(jù)儲存條件，適當保存；體內(nèi)實驗的作液，建議您現(xiàn)現(xiàn)配，當天使； 以下溶劑前顯的百分 指該溶劑在您配制終溶液中的體積占；如在配制過程中出現(xiàn)沉淀、析出現(xiàn)象，可以通過加熱和/或超聲的式助溶1. 請依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (6.69 mM); Clear solution此案可獲得 2.5 mg/mL (6.69 mM，飽和度未知) 的澄清溶液。以 1 mL 作液為例，取 100 L 25.

4、0 mg/mL 的澄 DMSO 儲備液加到 400 L PEG300 中，混合均勻；向上述體系中加50 L Tween-80，混合均勻；然后繼續(xù)加 450 L 理鹽定容 1 mL。2. 請依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (6.69 mM); Clear solutionPage 1 of 2 www.MedChemE此案可獲得 2.5 mg/mL (6.69 mM，飽和度未知) 的澄清溶液。以 1 mL 作液為例，取 100 L 25.0 mg/mL 的澄 DMSO 儲備液加到 900 L 2

5、0% 的 SBE-CD 理鹽溶液中，混合均勻。BIOLOGICAL ACTIVITY物活性 Motesanib 種有效的 VEGFR1/2/3 的 ATP 競爭性抑制劑，IC50 值為 2 nM/3 nM/6 nM，與對Kit的選擇性相似，是 PDGFR 和 Ret的 10 倍多。IC & Target VEGFR1 VEGFR2 VEGFR32 nM (IC50) 3 nM (IC50) 6 nM (IC50)體外研究 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.體內(nèi)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.戶使本產(chǎn)品發(fā)表的科研獻 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