沙普替尼作用机制 - Medchemexpress - MCE中国

1、Product Data SheetSapitinibCat. No.: HY-13050CAS No.: 848942-61-0分式: CHClFNO分量: 473.93作靶点: EGFR作通路: JAK/STAT Signaling; 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 : 33 mg/mL (69.63 mM)* means soluble, but saturation unknown.Solvent

2、Mass1 mg 5 mg 10 mgConcentration制备储备液1 mM 2.1100 mL 10.5501 mL 21.1002 mL5 mM 0.4220 mL 2.1100 mL 4.2200 mL10 mM 0.2110 mL 1.0550 mL 2.1100 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

3、下溶解案都请先按照 In 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 (5.28 mM); Clear solution此案可获得 2.5 mg/mL (5.28 mM，饱和度未知) 的澄清溶液。以 1 mL 作液为

4、例，取 100 L 25.0 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 (5.28 mM); Clear solutionPage 1 of 2 www.MedChemE此案可获得 2.5 mg/mL (5.28 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

5、储备液加到 900 L 20% 的 SBE-CD 理盐溶液中，混合均匀。3. 请依序添加每种溶剂： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (5.28 mM); Clear solution此案可获得 2.5 mg/mL (5.28 mM，饱和度未知) 的澄 溶液，此案不适于实验周 期在半个以上的实验。以 1 mL 作液为例，取 100 L 25.0 mg/mL 的澄 DMSO 储备液加到 900 L 油中，混合均匀。BIOLOGICAL ACTIVITY物活性 Sapitinib (AZD-8931)是可逆的，ATP竞争型 EGFR 抑制剂，对E

6、GFR，ErbB2 和 ErbB3的 IC50 值分别为4，3 和 4 nM。IC & Target EGFR ErbB2 HER34 nM (IC50) 3 nM (IC50) 4 nM (IC50)体外研究 AZD8931 shows potent inhibitory effect on erbB2 in the ligand-independent MCF-7 cl24 cells, with IC50 of 59 nM1.AZD8931 (1 M) has no significant effect on EGFR expression level, but significantl

7、y inhibits phosphorylation of Akt ina time- and dose-dependent manner in both SUM149 and FC-IBC-02 cells. AZD8931 (0.01, 0.1, 1, or 2 M) inhibitsproliferation and induces apoptosis in human IBC cells2. At the cellular level, AZD8931 inhibits EGF-stimulatedphosphorylation of EGFR in the KB cell line

8、(IC50: 4 nM) and heregulin-stimulated phosphorylation of HER2 (IC50: 3nM) and HER3 (IC50: 4 nM) in the MCF-7 cell line. However, AZD8931 exhibits no CYP P450 inhibition (IC50 10 Magainst 1A2, 2C9, 2C19, 2D6, and 3A4)3.体内研究 AZD8931 (6.25-50 mg/kg, p.o.) significantly inhibits BT474c (breast), Calu-3

9、(NSCLC), LoVo (colorectal), FaDu (SCCHN),and PC-9 (NSCLC) tumor xenograft growth. AZD8931 is active in xenograft tumor models responsive to EGFRinhibition alone (LoVo and PC-9) or EGFR or erbB2 inhibition (BT474c, Calu-3, and FaDu). AZD8931 causespharmacodynamic changes in proliferation and apoptosi

10、s markers in human tumor xenograft models1. AZD8931 (25mg/kg, p.o.) significantly inhibits the growth of SUM149 and FC-IBC-02 cells in vivo in SCID mice2. AZD8931 displaysfavorable oral pharmacokinetics in rat and dog (low clearance and good bioavailability) and low human hepatocyteturnover (Clint 4

11、.5 L/min/106 cells). In nude mouse after oral administration at 50 mg/kg, AZD8931 showsimproved exposure, and at at 100 mg/kg oral dose once daily, it shows potent tumor growth inhibition activity in theLoVo mouse xenograft model3.PROTOCOLCell Assay 1 Cells are incubated for 96 h with a suitable ran

12、ge of concentrations of drug to ensure accurate estimation of theinhibitor concentration required to give 50% growth inhibition (GI50; typically between 0.001-10 M). Viable cellnumber is determined by 4 h of incubation with MTS Colorimetric Assay reagent and absorbance measured at 490nm on a spectro

13、photometer. Each experiment is carried out in triplicate for each drug concentration and data arepresented as geometric means. Sensitivity groupings of GI50 data are 7 M.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Swiss nude (nu/nu genotype)

14、and severe combined immunodeficient mice are used. AZD8931, GW572016, andAdministration 1 ZD1839 are suspended in a 1% (v/v) solution of polyoxyethylenesorbitan monooleate (Tween 80) in deionized water.Animals are given AZD8931 (6.25-50 mg/kg), GW572016 (100 mg/kg), ZD1839 (100-150 mg/kg), or vehicl

15、e controlonce (qd) or twice daily (bid) by oral gavage. The duration of each study is determined by tumor growthcharacteristics, with studies ending once tumors reach 1 cm3. Tumor volume and percentage tumor growthPage 2 of 3 www.MedChemEinhibition are calculated and statistical analysis of any chan

16、ge in tumor volume is carried out using a standard t test(P value of lower then 0.05 is considered to be statistically significant).MCE has not independently 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. Mol Pharm

17、acol. 2019 Sep 25. pii: mol.119.117804.See more customer validations on HYPERLINK www.MedChemE www.MedChemEREFERENCES1. Hickinson DM, et al. AZD8931, an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor, ERBB2 (HER2), and ERBB3: a uniqueagent for simultaneous ERBB rec

18、eptor blockade in cancer. Clin Cancer Res. 2010 Feb 15;16(4):1159-69.2. Mu Z, et al. AZD8931, an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor (EGFR), HER2, and HER3: preclinical activity inHER2 non-amplified inflammatory breast cancer models. J Exp Clin Cancer Res. 2014 M