| 名称 | Capmatinib 2HCl |
| 描述 | Capmatinib 2HCl (INC-280 2HCl) is a novel, ATP-competitive inhibitor of c-MET kinase with an IC50 with 0.13 nM.Capmatinib 2HCl exhibits picomolar enzymatic potency and is highly specific for c-MET with more than 10, 000-fold selectivity over a large panel of human kinases. This inhibitor potently blocks c-MET phosphorylation and activation of its key downstream effectors in c-MET-dependent tumor cell lines. As a result, Capmatinib 2HCl potently inhibits c-MET-dependent tumor cell proliferation and migration and effectively induces apoptosis in vitro. |
| 细胞实验 | Cell lines: H441 cells. Concentrations: 0.24,1,4,16,63 nM. Incubation Time: 24 hours. Method:H441 cells are seeded in RPMI-1640 medium containing 10% FBS and grown to complete confluence.Gaps are introduced by scraping cells with a P200 pipette tip.Cells are then stimulated with 50 ng/mL recombinant human HGF to induce migration across the gap in the presence of various concentrations of INCB28060.After an overnight incubation,representative photographs are taken and a semiqualitative assessment of inhibition of cell migration is conducted. |
| 激酶实验 | c-Met Kinase Assay:The assay buffer contains 50 mM Tris-HCl, 10 mM MgCl2, 100 mM NaCl, 0.1 mg/ml BSA, 5 mM DTT, pH 7.8. For HTS 0.8 μL of 5 mM of INCB28060 dissolved in DMSO are dotted on 384-well plates. DMSO titration suggests that the maximum tolerated concentration of the solvent is 4%. To measure IC50s the INCB28060 plate is prepared by 3-fold and 11-point serial dilutions. 0.8 μL of INCB28060 in DMSO is transferred from INCB28060 plate to the assay plate. The final concentration of DMSO is 2%. Solutions of 8 nM unphosphorylated c-Met or 0.5 nM phosphorylated c-Met are prepared in assay buffer. A 1 mM stock solution of peptide substrate Biotin-EQEDEPEGDYFEWLE-amide dissolved in DMSO is diluted to 1 μM in assay buffer containing 400 μM ATP (unphosphorylated c-Met) or 160 uM ATP (phosphorylated c-Met). A 20 μL volume of enzyme solution (or assay buffer for the enzyme blank) is added to the appropriate wells in each plate and then 20 μL/well of substrate solution to initiate the reaction. The plate is protected from light and incubated at 25 °C for 90 minutes. The reaction is stopped by adding 20 μL of a solution containing 45 mM EDTA, 50 mM Tris-HCl, 50 mM NaCl, 0.4 mg/ml BSA, 200 nM SA-APC and 3 nM EUPy20. The plate is incubated for 15-30 minutes at room temperature and HTRF (homogenous time resolved fluorescence) is measured on a Perkin Elmer Fusion α-FP instrument. The HTRF program settings used are as follows: Primary excitation filter 330/30, Primary window: 200 uSec, Primary delay: 50 uSec, Number of flashes: 15, Well read time: 2000 |
| 动物实验 | Animal Models: Eight-week-old female Balb/c nu/nu mice (Charles River) are inoculated subcutaneously with 4 × 106 tumor cells (S114 model) or with 5 × 106 tumor cells (U-87 mg glioblastoma model). Formulation: INCB28060 is prepared as a 5 mM stock solution in 100% dimethyl sulfoxide and routinely stored at room temperature. Dosages: 3,10,30 mg/kg. Administration: INCB28060 is orally dosed,twice each day. |
| 体外活性 | Capmatinib(free base) 在酶促活性方面表现出皮可摩尔级的效能，并且对于c-MET具有极高的特异性，其选择性比人类大量激酶高出10000倍以上。Capmatinib抑制了人类c-MET的磷酸化和c-MET介导的癌细胞信号传导。此外，Capmatinib阻止了依赖c-MET的细胞增殖和生存，避免了癌细胞在无基底的条件下生长和细胞迁移。 |
| 体内活性 | INCB28060（free base）在依赖c-MET的小鼠肿瘤模型中展现出强大的抗肿瘤活性，即使是0.03 mg/kg的口服剂量也能导致c-MET磷酸化约50%的抑制。在携带肿瘤的小鼠中观察到了剂量依赖性的肿瘤生长抑制。 |
| 存储条件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | DMSO : 11 mg/mL (22.66 mM)
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| 关键字 | Apoptosis | c-Met/HGFR | H441 | Capmatinib 2HCl | orally active | SNU-5 | INCB28060 | Inhibitor | INCB 28060 | S114 | INC280 | inhibit | INC 280 | Capmatinib | INCB-28060 | U-87MG | ATP competitive | INC-280 | Balb/c nu/nu mice |
| 相关产品 | Cabozantinib S-malate | Crizotinib | Amuvatinib | BMS 777607 | (±)-Norcantharidin | Capmatinib xHCl | LMTK3-IN-1 | L-Ascorbic acid 2-phosphate trisodium | Norcantharidin | Bacitracin Zinc | AMG-458 | SU11274 |
| 相关库 | 抑制剂库 | 抗癌活性化合物库 | 抗癌上市药物库 | 已知活性化合物库 | 激酶抑制剂库 | FDA 上市药物库 | 膜蛋白靶向化合物库 | FDA 上市激酶抑制剂库 | 抗癌临床化合物库 | 抗癌药物库 |